Sertraline salts and sustained-release dosage forms of sertraline

ABSTRACT

Sustained release dosage forms of sertraline which release sertraline at a rate between 1 mgA/hr and 40 mgA/hr. The dosage forms may exhibit an initial delay period during which sertraline is released at a rate less than 1 mgA/hr.

This is a National Stage filing under 35 USC §371 based onPCT/IB98100934, which was filed internationally on Jun. 15, 1998 andwhich claims priority from U.S. provisional applications 60/051,498filed Jul. 1, 1997; 60/051,420 filed Jul. 1, 1997; 60/051,414 filed Jul.1, 1997; and 60/051,402 filed Jul. 1, 1997.

FIELD OF THE INVENTION

This invention relates to certain salts of sertraline, and to asustained-release dosage form of sertraline having an improved sideeffect profile, and to a method of treating a psychiatric or otherillness comprising administering sertraline in such a sustained-releasedosage form to a mammal, including a human patient, in need of suchtreatment

BACKGROUND OF THE INVENTION

Sertraline is a selective serotonin reuptake inhibitor (SSRI), which isuseful, inter alia, as an antidepressant and anorectic agent, and in thetreatment of obsessive-compulsive disorder, premenstrual dysphoricdisorder, post-traumatic stress disorder, chemical dependencies,anxiety-related disorders, panic and premature ejaculation. See U.S.Pat. No. 4,536,518, Published International Application WO 92/18005,U.S. Pat. No. 5,130,338, U.S. Pat. No. 4,971,998, PublishedInternational Application WO 92/00103, U.S. Pat. No. 5,061,728, U.S.Pat. No. 4,940,731, and U.S. Pat. No. 4,962,128, each of which isincorporated herein by reference. Sertraline is also known as(1S-cis)-(4-(-3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine,has the empirical formula C₁₂H₁₇NCl₂, and has the structural formula

Sertraline is most commonly prescribed for therapy of depressiveillness, in the general dose range 50-200 mg/day. Sertraline has anelimination half-life of 23 hr, and is dosed once daily.

Patients are generally initiated on sertraline at a dose of 50 mg/day.Patients who do not respond at the 50 mg dose are given higher doses.Initiation at doses greater than 50 mg is generally avoided, whenpossible, because side effects such as dizziness, tremor, and sweating,and gastrointestinal upset are generally believed to be more severe athigher doses. If necessary to achieve efficacy, higher doses may bereached by slow titration up from lower doses. Improved sertralinedosage forms which exhibited a lower incidence and/or severity of sideeffects would be advantageous because (1) patient comfort would beimproved, and (2) dosing could be initiated at doses higher than 50 mg.without the need for dose titration. Initiation at higher starting doseswould, in turn, be useful by potentially effecting a shorter onset ofantidepressive action. Thus, such an improved sertraline dosage formwhich permitted oral dosing of high doses of sertraline (e.g., 200 mgand higher) with relatively reduced side effects would permit widertherapeutic application of sertraline therapy, and would accordinglyprovide a significant improvement in dosing compliance and convenience.Likewise, an improved dosage form which lowered the incidence and/orseverity of side-effects at lower doses would also be of significantvalue.

SUMMARY OF THE INVENTION

This invention provides an oral, sustained release dosage form ofsertraline which decreases, relative to currently marketed instantrelease sertraline tablet dosage forms which deliver an equivalent bolusdose, the incidence and/or severity of gastrointestinal and/or otherside effects such as dizziness, tremor and sweating. The dosage formoperates by effecting the release of sertraline at a rate sufficientlyslow to ameliorate side effects.

Dosage forms which release more than 70% of their contained sertralinewithin one hour or less are not “sustained release”, and form no part ofthis invention. This feature thus excludes from the invention immediaterelease dosage forms containing 40 mg of sertraline or less. Such dosageforms will technically release sertraline at a rate less than 40 mgA/hr,but are excluded because they do not do so in a sustained manner.

In one aspect this invention provides a sustained-release dosage formsuitable for administration to a mammal, comprising sertraline, or apharmaceutically salt thereof, and a pharmaceutically acceptablecarrier,

which dosage form releases sertraline into a use environment at a ratenot exceeding 0.8 mgA/hr/kg, preferably at a rate not exceeding 0.7mgA/hr/kg,

provided said dosage form (1) releases not more than 70% of thesertraline contained therein within the first hour following entry intosaid use environment and (2) releases sertraline at a rate of at least0.02 mgA/hr/kg. This aspect of the invention describes a dosage formwithout regard to the size of any particular mammal.

In another aspect this invention provides a sustained-release dosageform suitable for oral administration to a mammal, comprisingsertraline, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier,

which dosage form releases sertraline into a use environment at a ratenot exceeding 40 mgA/hr,

provided said dosage form (1) releases not more than 70% of thesertraline contained therein within the first hour following entry intosaid use environment and (2) releases sertraline at a rate of at least 1mgA/hr. This aspect of the invention describes a dosage form suitablefor administration to mammals such as average size adult humans. Adosage form according to the invention thus releases sertraline at arate of from 1 to 40 mgA/hr. Particular release rate ranges includerates of from 2 to 40 mgA/hr, 3 to 40 mgA/hr, 1 to 30 mgA/hr, 2 to 30mgA/hr, and 3 to 30 mgA/hr. The ranges 1 to 30 mgA/hr and 2 to 30 mgA/hrare preferred. The ranges 1 to 25 mgA/hr and 2 to 25 mgA/hr are morepreferred.

Reference to a dosage form which “releases” sertraline means (1) releaseof sertraline to a mammal's gastrointestinal (GI) tract followingingestion or (2) release of sertraline into an in vitro test medium foranalysis by an in vitro test as described below. Reference to a “useenvironment” can thus be either to in vivo gastrointestinal fluids or toin vitro test medium.

Rates of sertraline release lower than 25, 30 or 40 mgA/hr are alsowithin the scope of the invention and may produce even better sideeffect profiles, particularly for patients under 50 kg weight forexample children. Thus a sertraline release rate of 7 mgA/hr afteringestion represents a release profile within the scope of the inventionand may be even more efficacious for ameliorating side effects. The ratemust, of course, be high enough to provide therapeutic efficacy, thatis, a therapeutically sufficient amount of sertraline should bedelivered from the dosage form before the dosage form is excreted withthe feces. Accordingly, dosage forms according to the invention shouldrelease sertraline at a rate of at least 1 mgA/hr.

The unit “kg” as used herein in “mgA/hr/kg” refers to kilograms of bodyweight for the mammal being treated.

It is noted that the mouth-to-anus transit time of a non-disintegrating(e.g., tablet or multiparticulate) dosage form is approximately 24hours. Dosage forms of this invention release at least 6%, preferably atleast 70%, of their contained sertraline within 24 hour. Absorption ofsertraline from the lower gastrointestinal (GI) tract, especially fromthe colon, is less efficient than absorption from the upper GI tract,i.e., from the small intestine, as shown in Example 3. It is accordinglytherapeutically advantageous to deliver less sertraline in the lower GItract and more sertraline in the upper GI tract. Accordingly, controlledrelease sertraline dosage forms according to the invention release atleast 60%, preferably at least 70%, of their contained sertraline within24 hours, preferably within 18 hours, most preferably within 16 hours.

Although dosage forms as defined above generally release at least 70% oftheir contained sertraline within 24 hours, a dosage form according tothe invention can release substantially all of its sertraline wellbefore 24 hours so long as it otherwise releases sertraline at a ratenot exceeding 40 mgA/hr or 0.8 mgA/hr.

The term “ingestion” as used herein is essentially synonymous with“swallowing”.

The invention is particularly useful for administering relatively largeamounts of sertraline to a patient. The amount of sertraline containedwithin the dosage form is preferably at least 10 mgA, and can be as highas 500 mgA or more. The amount contained in the dosage form is morepreferably 25 mgA to 400 mgA. The dosage form can be unitary or dividede.g., constituted by two or more units (such as capsules or tabletswhich, taken together, constitute the dosage form) which are taken at orabout the same time.

Sertraline can be employed in the dosage forms of this invention in theform of its pharmaceutically acceptable salts, and also in anhydrous aswell as hydrated forms. All such forms can be used within the scope ofthis invention. The sertraline employed is preferably the free base,hydrochloride, aspartate, acetate, or lactate salts. For convenience andconsistency, reference to “sertraline” in terms of therapeutic amountsor in release rates in the claims is to active sertraline, abbreviatedherein as “mgA”, i.e., the non-salt, nor-hydrated free base having amolecular weight of 306.2. Amounts in mgA can conveniently be convertedto equivalent weights for whatever salt form is desired.

The dosage forms which constitute the subject matter of the inventionare, as mentioned, sustained release formulations. The dosage form canbe in the form of a tablet, a capsule, a multiparticulate form, amultiparticulate form in a tablet or capsule, or a unit dose packet(sometimes referred to in the art as a “sachet”). Also included arecombination dosage forms, for example those comprising one or moresustained release tablets contained within a capsule shell such as agelatin capsule shell.

The term “tablet” is intended to embrace compressed tablets, coatedtablets, matrix tablets, osmotic tablets, and other forms known in theart, and as more fully disclosed and described below,

The term “capsule” is intended to embrace capsules in which the body ofthe capsule disintegrates after ingestion to release particulatecontents which exhibit the desired sustained-release behavior, and alsocapsules for which the body of the capsule remains substantially intactduring its residence in the GI tract.

In a further aspect this invention provides a method for treating apsychiatric or other illness, comprising administering to a mammal inneed of such treatment, including a human patient, a therapeuticallyeffective amount of sertraline in a sustained-release oral dosage formwhich releases the sertraline according to the release rate describedabove. Such illnesses include those known in the art as being treatablewith sertraline, including those mentioned above.

In a further aspect, this invention provides a sustained release dosageform suitable for administration to a mammal, comprising sertraline or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier, which dosage form releases sertraline in vitro at arate less than 40 mgA/hr, when dissolution tested in a USP-2 apparatuscontaining a test medium comprising 900 ml of acetate buffer, pH 4.0,which is 0.075 M in NaCl, at 37° C., as follows:

(1) if said dosage form is a sustained release tablet or anon-disintegrating sustained release capsule, said USP-2 apparatus isequipped with a paddle stirring at 50 rpm; or

(2) if said dosage form is a multiparticulate, said USP-2 apparatus isequipped with a paddle stirring at 100 rpm;

provided said dosage form (a) releases not more than 70% of thesertraline contained therein within the first hour following initiationof testing and (b) releases sertraline at a rate of at least 1 mgA/hr.

Examples of dosage forms which fall into category (1) above include:

a. sustained release reservoir tablets such as coated diffusive tablets,osmotic tablets, and membrane coated swelling hydrogel tablets;

b. matrix tablets, both disintegrating and non-disintegrating; and

c. non-disintegrating capsules; The capsule shell material should be anon-gelatin polymer such as ethylcellulose or cellulose acetate.

Examples of dosage forms which fall into category (2) above include unitdose packets (also known in the art as “sachets”) and powders for oralsuspension. Ideally, each particle in a multiparticulate constitutes aself-contained unit of sustained release. The particles can be formedinto larger units as by being compressed into a larger tablet-like unitwhich is more convenient for swallowing. The larger units disintegraterapidly upon swallowing to give rise to the multiparticulate form,however.

It is noted that the term “multiparticulate” means a plurality ofparticles wherein each particle is designed to yield controlled releaseof sertraline. Ideally, each particle in a multiparticulate constitutesa self-contained unit of sustained release. The particles can be formedinto larger units. The multiparticulate particles each comprisesertraline and one or more excipients as needed for fabrication andperformance. The size of individual particles is generally between about50 μm and about 3 mm. A multiparticulate predominantly composed ofparticles toward the low end of this size range is sometimes referred toherein as a powder. Multiparticulates predominantly composed ofparticles toward the high end of the size range are sometimes referredto herein as beads. Beads having a size outside this range may also beuseful.

Any of the dosage forms in (1) or (2) above can be incorporated into agelatin capsule. If the dosage form is in a gelatin capsule or otherwisegelatin coated, then the dosage form is tested in a USP-2 paddleapparatus as described in (1) or (2), as appropriate depending on theexact dosage form, but with trypsin added to the acetate buffer to aconcentration of 0.1 mg/mL. Generally, the amount of or size of thedosage form tested should contain or be equivalent to 200 mgA ofsertraline or less. If the dosage form contains more than 200 mgA, thenthe amount of acetate buffer test medium should be increasedproportionately.

The test solution employed above is an acetic acid/acetate buffersolution, pH 4.0, which buffer is 0.075 M in NaCl, and which is intendedto simulate gastrointestinal fluids. The test solution is made by makinga 0.13M solution of acetic acid in water and then making this solutioninto an acetic acid/acetate buffer by adding potassium hydroxide,typically as an 0.5M aqueous solution, until a pH of 4.0 has beenattained. Sufficient sodium chloride is then added to make the solution0.075M in NaCl. The temperature of the test solution is maintained at 37C throughout the dissolution test.

The in vitro release rate is determined by multiplying the incorporateddose by 0.8, and dividing this number by the measured time at which 80%of the incorporated dose has been released and dissolved, as furtherdiscussed below. If 80% of the incorporated sertraline is not releasedin 24 hr, then the mgA sertraline released at 24 hr should be divided by24 hr, to give the release rate. Further, no more than 40 mgA isreleased in any one hour. This aspect of the invention thus defines asustained release dosage form by means of a conveniently performed invitro test conducted in a standard, well known apparatus. As previouslymentioned, not more than 40 mgA should be released in any one hour ofthe test. It is noted that a USP-2 apparatus, equipped with a paddle, iswell known and described in United States Pharmacopoeia XXIII (USP)Dissolution Test Chapter 711, Apparatus 2.

A unitary dosage form is dissolution tested by placing it in apaddle-equipped USP-2 apparatus containing 900 ml of be test solutionjust described, the test solution having a temperature of 37 deg C, withthe paddle stirring at 50 rpm. If the dosage form is a capsule, it istested in the same manner except that the test solution is augmented tocontain 0.1 mg/mL of trypsin. Filtered aliquots (typically 2 or 10 mL)of the dissolution medium are taken at various times, referred to hereinas “pull points.” The exact time at which an aliquot is removed is notparticularly critical, although pull points may be standardized forconvenience. The aliquot is filtered and assayed for sertraline contentutilizing an HPLC assay or other suitable assay. The data is plotted asmgA sertraline (active sertraline) released (or % sertraline basereleased) on the y-axis vs time on the x-axis. The time at which 80% ofthe sertraline dose is released is noted.

To assure accuracy of results, more than one, for example three, or morepreferably six, separate dissolution tests should be conducted and therates determined and averaged.

As mentioned above, an in vitro release rate is calculated from thedissolution test by dividing the quantity of sertraline corresponding to80% release (determined by multiplying the incorporated dose by 0.8) bythe time it takes to effect the 80% release. For example, if a 100 mgAsertraline oral dosage form is tested in this fashion, and 80% of theincorporated sertraline is released in 8 hr, then the release rate is(100 mg×0.8)/18 hr, or 10 mgA/hr. This dosage form is thus within thescope of this invention. As another example, if a 50 mgA sertraline oraldosage form is tested in vitro, and 80% of the incorporated sertraline(as sertraline base) is released in 0.4 hr, then the release rate is (50mg×0.8)/0.4 hr, or 100 mgA/hr, and the dosage form is not within thescope of the invention.

While there are many methods of describing the in vitro-rate of drugrelease from a dosage form (e.g. first-order rate constant zero-orderrate constant, initial rate, etc.), the method described above providesa clear test which is independent of the mechanism of sertraline releasefrom the dosage form.

It is noted that immediate release sertraline dosage forms are known andcommercially available (ZOLOFT®, registered trademark of Pfizer Inc.) as50 mgA and 100 mgA strength tablets. When 50 mgA ZOLOFT tablets wereevaluated using the in vitro dissolution test described above, anaverage of 80% of the contained sertraline was released (i.e., dissolvedin the test fluid) at 0.7 hr after the start of the dissolution test.Thus the immediate release 50 mgA tablet released sertraline at a rateof 57 mgA/hr, calculated by the method described above. When two 100 mgAZOLOFT tablets (total dose 200 mgA) were evaluated by the abovedissolution test, 80% of the contained sertraline was released at 1.2 hrafter starting the test. Thus each 100 mg tablet released sertraline arate of 67 mg/hr and release for the 200 mg dose was 134 mg/hr,calculated by the method described above. Thus as the above in vitrotest illustrates, such dosage forms are outside the scope of thisinvention.

In a further aspect, this invention provides a sustained release dosageform of sertraline suitable for oral administration to a mammal, whichresults in a maximum sertraline plasma concentration, C_(max), which isless than 80% of the C_(max) determined when an equal dose of sertralineis orally administered in the form of an immediate release bolus (suchas an immediate-release tablet). This aspect of the invention defines asustained release dosage form according to the invention by means of anappropriate in vivo test which is conducted in the mammalian species ofinterest. For example, to test whether a sustained release oralsertraline dosage form ameliorates side effects in humans, thesertraline test dosage form is dosed to half of a group of 12 or morehumans and, after an appropriate washout period (e.g. 1 week) the samesubjects are dosed with an immediate-release bolus dose at the samestrength. The other half of the group is dosed with theimmediate-release bolus dose first, followed by the sertraline(sustained-release) test dosage form and the plasma sertraline levelsare measured as a function of time. After determining C_(max) for eachindividual on each treatment, an average C_(max) is determined. IfC_(max) for the sustained release sertraline test dosage form is lessthan 80% of the C_(max) for the bolus dose, then the test dosage formwill provide a side effect improvement over the bolus dosage form and iswithin the scope of the invention. In this embodiment, the dosage formmay be sustained release, engineered with or without an initial delayperiod, as disclosed below. It is noted that “immediate release” meansthe bolus has not been engineered to include a means for slowingdisintegration or dissolution of the dosage form.

Dosage forms which pass either an in vitro test relating thereto asdescribed herein, or an in vivo test relating thereto as describedherein (including the C_(max) test just described, are within the scopeof the invention, as are dosage forms which pass all such tests relatingthereto.

As stated above, sustained release sertraline dosage forms provide adecreased C_(max) relative to the C_(max) for immediate-release dosageforms containing equal amounts of sertraline. That is, sustained-releasedosage forms exhibit a C_(max) which is less than or equal to 80% of theC_(max) provided by an equivalent immediate release dose. Preferreddosage forms additionally provide a total blood drug exposure whichagain, relative to equivalent immediate-release dosage forms, is notproportionately decreased as much as the sustained release C_(max). A“total blood drug exposure” is determined as AUC, the area under thecurve determined by plotting the concentration of drug in the plasma(Y-axis) vs. time (X-axis). AUC is generally an average value, and wouldfor example be averaged over all the subjects in the crossover studydescribed above. The determination of AUCs is a well known procedure,and is described, for example, in “Pharmacokinetics; Processes andMathematics,” by Peter Welling (ACS Monograph 185, Amer. Chem. Soc.,Wash. D.C.: 1986). By way of example, suppose a sustained release 100mgA sertraline dosage form A exhibits a C_(max) that is 65% of theC_(max) produced by a 100 mgA immediate release sertraline bolus. In apreferred embodiment, sustained release dosage form A will also exhibitan AUC that is higher than 65% of that provided by the bolus.

In a further aspect the invention provides a sertraline sustainedrelease dosage form which exhibits an initial delay in sertralinerelease when the dosage form enters its environment of use, i.e. afteringestion, followed by sustained sertraline release as described above.During the delay period essentially no sertraline is released, although“essentially no sertraline” includes very small release rates less than1 mgA/hr. This type of dosage form is sometimes referred to herein as a“delayed plus sustained releases” dosage form. The inventors havedemonstrated that certain side effects of sertraline, namely nausea,regurgitation, and diarrhea, are partially or primarily mediated bydirect contact of sertraline with the upper gastrointestinal tract,primarily the stomach, rather than mediated systemically, that is viaexposure of sertraline to the bloodstream after absorption. Prior to thehuman clinical studies carried out by the inventors (presented asExample 6 below), the locally mediated nature of these three sertralineside effects was not known. Thus advantageous sertraline dosage forms ofthis invention include dosage forms which exhibit a spatial or temporaldelay in sertraline release after ingestion. Sustained releasesertraline dosage forms which exhibit a spatial delay include thosewhich are sensitive to their position along the GI tract, which areindependent of time, and which possess a mechanism that largely orcompletely prevents release of sertraline in the stomach, and which thencommence sustained release after the dosage form has passed into theduodenum. Once having commenced sustained release of sertraline, thesustained release is restricted in rate and extent as closed above for“non-delayed” sustained release sertraline dosage forms.Spatially-delayed sustained release dosage forms of this inventioncommence sustained release of sertraline within approximately 30minutes, preferably within approximately 15 minutes, of passing out ofthe stomach into the duodenum.

Temporally-delayed sustained release sertraline dosage forms accordingto the invention are those which, after ingestion, exhibit a temporaldelay before commencing sustained sertraline release. By a temporaldelay in this context is meant a delay following ingestion which is notrelated to the spatial location of the dosage form in the GI tract.Temporally-delayed sustained release sertraline dosage forms exhibit adelay of up to 3 hours after ingestion, preferably up to 2 hours, mostpreferably up to 1.5 hours. This temporal delay minimizes the exposureof the upper gastrointestinal tract, particularly the stomach, tosertraline after oral ingestion, thus ameliorating locally mediated sideeffects. After the delay, the dosage form releases sertraline in amanner restricted in rate and extent as disclosed above for“non-delayed” sustained release sertraline dosage forms.

It is noted that in the claims, reference to a “sustained release dosageform” is to a dosage form not having an initial delay period implementedtherein. Reference in the claims to dosage forms having a period ofdelay implemented therein are specific in pointing this out, for exampleas to a “sustained release dosage form having an initial delay period”,to a temporally or spatially “delayed plus sustained release dosageform”, or similar language such as “said dosage form having an initialdelay period.”

It is noted that there is a natural lag period, usually not more than 15minutes following ingestion, during which time the dosage form iswetted, hydrated, and otherwise affected by bodily (GI) fluids so thatit can start to dissolve and release sertraline. This typical lag orinduction period of about ten minutes during which wetting occurs issubsumed under the delay period engineered into the dosage form, suchthat the delay period can also be thought of as about 15 minutes up to 3hours, preferably about 15 minutes up to 2 hours. If the induction orlag time is not more than 15 minutes, it is not considered to be delayedplus sustained release. Rather, it is simply sustained release.

Thus this invention provides a temporally delayed plus sustained releasedosage form suitable for administration to a mammal, comprisingsertraline or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier,

which dosage form, following ingestion by said mammal, releasessertraline into said mammal's GI tract at a rate less than 1 mgA/hr foran initial delay period of up to three hours, preferably of up to twohours, more preferably of up to 1.5 hr,

and which thereafter releases sertraline at a rate of from 1 mgA/hr to40 mgA/hr, provided said dosage form releases not more than 70% of thesertraline contained therein within the first hour after said delayperiod.

The dosage form can also be a spatially delayed plus sustained releasedosage form suitable for oral administration to a mammal, comprisingsertraline or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier,

which dosage form, following ingestion by said mammal, releasessertraline into said mammal's stomach at a rate less than 1 mgA/hr,

and which, after having passed into said mammals duodenum; releasessertraline at a rate-of from 1 mgA/hr to 40 mgA/hr, provided said dosageform releases not more man 70% of the sertraline contained thereinwithin the first hour after passing into said mammal's duodenum.

The following in vitro tests can be used to determine whether or not aparticular dosage form falls within the scope of the invention,depending on whether the onset of the sustained release component istemporally or spatially delayed.

If the dosage form is temporally delayed, the in vitro test can beconducted exactly as previously described for sustained release dosageforms which do not have a temporal delay incorporated therein. Thedosage form will release sertraline at a rate less than 1 mgA/hr for aperiod of up to three hours, or less, corresponding to the length of thedelay period, followed by sustained sertraline release at a rate of from1 mgA/hr to 40 mgA/hr thereafter. Conditions, test apparatus, and testmedium can otherwise be the same as for pure sertraline sustainedrelease dosage forms. As with other dosage forms, dosage forms with atemporal delay release not more than 70% of the remaining sertralinecontained therein within the first hour following said delay.

If the dosage form is spatially delayed with a pH-trigger, the inventionprovides a sustained release pH-triggered dosage form suitable for oraladministration to a mammal, said dosage form having an initial delayperiod prior to the onset of sustained release, comprising sertraline ora pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier, which dosage form, when tested in vitro in a USP-2apparatus,

releases sertraline into 0.1 N HCl at a rate less than1 mgA/hr for atleast 1 hour and, thereafter,

releases sertraline into phosphate buffer, pH 6.8 containing 1%polysorbate 80 at a rate of from 1 mgA/hr to 40 mgA/hr, provided thedosage form releases not more than 70% of the remaining sertralinecontained therein within the first hour following said delay.

If the dosage form is spatially-delayed with an enzyme-trigger, theinvention provides an oral sustained release enzyme-triggered dosageform-suitable for administration to a mammal, said dosage form having aninitial delay period prior to the onset of sustained release, comprisingsertraline or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier, which dosage form, when tested invitro in a USP apparatus

releases sertraline into 0.1 N HCl at a rate less than 1 mgA/hr for aperiod of at least 1 hour and, thereafter,

releases sertraline at a rate of from 1 mgA/hr to 40 mgA/hr intophosphate buffer, pH 6.8, containing 1% polysorbate 80 and in thepresence of an enzyme suitable for triggering the onset of saidsustained release, provided the dosage form releases not more than 70%of the remaining sertraline contained therein within the fist hourfollowing said delay.

In these in vitro tests, 1 mgA/hr is calculated as the average hourlyquantity of sertraline released, calculated over the initial 1 hr orlonger time period of the test corresponding to the delay period.

It is an object of this invention to decrease the incidence and severityof sertraline-induced side effects. This s particularly important athigh doses, for example 100 mg and up, at which the incidence of sideeffects can be higher. This object is effected, inter alia, bycontrolling the rate and degree of exposure of the gastrointestinaltract and the systemic circulation to sertraline, in at least a portionof sertraline-dosed patients, thereby reducing the overall incidence andseverity of sertraline-induced side effects.

It is noted that sustained-release dosage forms of various types areknown and employed conventionally in the art to provide reduced dosingfrequency for short half-life compounds and to reduce fluctuations inplasma concentrations, sometimes imparting an improved safety/efficacyprofile due to avoidance of multiple plasma drug concentration peaks andtroughs throughout the day. Because elimination of sertraline from thehuman body is characterized by a long half-life of about 23 hours,however, it is surprising that a sustained-release dosage form wouldoffer any benefit.

The present invention further provides a new and useful acetate salt ofsertraline, hereinafter referred to as “sertraline acetate,”pharmaceutical compositions containing sertraline acetate; methods ofusing sertraline acetate and processes for preparing sertraline acetate.

The present invention further provides a new and useful L-lactate saltof sertraline, hereinafter referred to as “sertraline L-lactate,”pharmaceutical compositions containing seine L-lactate, methods of usingsertraline L-lactate and processes-for preparing sertraline L-lactate.

The present invention further provides a new and useful L-aspartate saltof sertraline, hereinafter referred to as “sertraline L-aspartate,”pharmaceutical compositions containing sertraline L-aspartate, methodsof using sertraline L-aspartate and processes for preparing sertralineL-aspartate.

The instant acetate salt of sertraline is highly water soluble and assuch is particularly well-suited for use in a controlled release, forexample, sustained release, encapsulated solution or delayed release,dosage form of sertraline. Further, sertraline acetate has advantageousmechanical properties and is chemically and physically stable. Theseproperties permit easy handling of sertraline during formulation ofdosage forms and result in tablets which are physically and chemicallysable during storage and use.

The instant L-lactate salt of sertraline is highly water soluble and assuch is particularly well-suited for use in a controlled release, forexample, sustained release, encapsulated solution or delayed release,dosage form of sertraline. Further, sertraline L-lactate hasadvantageous mechanical properties and is chemically and physicallystable. These properties permit easy handing of sertraline duringformulation of dosage forms and result in tablets which are physicallyand chemically stable during storage and use.

The instant L-aspartate salt of sertraline is highly water soluble andas such is particularly well-suited for use in a controlled release, forexample, sustained release, encapsulated solution or delayed release,dosage form of sertraline.

Thus the present invention is directed, inter alia, to sertralineacetate.

The present invention is particularly directed to sertraline acetatehaving the X-ray crystal structure depicted in FIG. 1 and the atomiccoordinates recited in Table 40-2.

The present invention is still further directed to sertraline acetate·¼hydrate.

The present invention is also directed to a method for treating anorexiain a subject suffering from anorexia or the symptoms of anorexiacomprising administering to said subject an effective amount ofsertraline acetate.

The present invention is also directed to methods for treating impulsedisorders such as trichotillomania, pathological gambling, kleptomaniaand pyromania in a subject suffering from one of said impulse disorderscomprising administering to said subject an effective amount ofsertraline acetate.

The present invention is also directed to methods for treatingonychophagia in a subject suffering from onychophagia comprisingadministering to said subject an effective amount of sertraline acetate.

The present invention is also directed to methods for treatingpremenstrual syndrome (also referred to herein as “premenstrualdysphoric disorder”) in a subject suffering from premenstrual syndromecomprising administering to said subject an effective amount ofsertraline acetate.

The present invention is also directed to methods for treating psychoticdisorders of the schizophrenic type in a subject suffering from saidpsychotic disorders or suffering from such symptoms as anxiety,agitation, tension, excessive aggression, social withdrawal or emotionalwithdrawal comprising administering to said subject an effective amountof sertraline acetate.

The present invention is also directed to methods for treatinginflammatory disorders such as psoriasis and arthritis in a subjectsuffering from an inflammatory disorder or inflammatory disorderscomprising administering to said subject an effective amount ofsertraline acetate.

The present invention is also directed to methods for treatingconditions characterized by a hyperactive immune system such asrheumatoid arthritis and lupus in a subject suffering from saidconditions comprising administering to said subject an effective amountof sertraline acetate.

The present invention is also directed to methods for treating mentaldepression in a mentally-depressed subject comprising administering tosaid subject an effective amount of sertraline acetate.

The present invention is also directed to methods for treatinganxiety-related disorders such as panic disorder, generalized anxietydisorder, agoraphobia, simple phobias, social phobia, posttraumaticstress disorder, obsessive-compulsive disorder and avoidant personalitydisorder in a subject suffering from one or more of said anxiety-relateddisorders comprising administering to said subject an effective amountof sertraline acetate.

The present invention is particularly directed to methods for treatinganxiety-related disorders as described in the previous paragraph whereinsaid anxiety-related disorder is obsessive-compulsive disorder.

The present invention is also directed to methods for treating chemicaldependency in a subject suffering from chemical dependency comprisingadministering to said subject an effective amount of sertraline acetate.

The present invention is further directed to pharmaceutical compositionscomprising sertraline acetate and a pharmaceutically acceptable carrieror diluent

The present invention is still further directed to pharmaceuticalcompositions comprising sertraline acetate having the X-ray crystalstructure depicted in FIG. 1 and a pharmaceutically acceptable carrieror diluent.

The present invention is also directed to processes for preparingsertraline acetate comprising reacting a salt of sertraline with a basein the presence of a suitable organic solvent to form sertraline freebase, partitioning said sertraline free base into an organic solvent andreacting said sertraline free base with acetic acid in the presence of asuitable organic solvent.

The present invention is particularly directed to processes as describedin the immediately preceding paragraph wherein said salt of sertralineis sertraline hydrochloride.

The present invention is more particularly directed to processes asdescribed in the immediately preceding paragraph wherein said solvent ishexane.

The present invention is further directed to processes for preparingsertraline acetate comprising reacting sertraline free base with aceticacid in the presence of a suitable organic solvent

The present invention is particularly directed to processes as describedin the immediately preceding paragraph wherein said solvent is hexane.

The present invention is also directed to processes for preparingsertraline acetate comprising reacting a salt of sertraline with a basein the presence of a suitable organic solvent to form sertraline freebase, partitioning said sertraline free base into an organic solvent andreacting said sertraline free base with acetic acid in the presence of asuitable organic solvent and isolating said sertraline acetate from saidsolvent.

The present invention is also directed to sertraline L-lactate.

The present invention is particularly directed to a form of sertralineL-lactate having the X-ray crystal structure depicted in FIG. 3 and theatomic coordinates recited in Table 48-2.

The present invention is also directed to methods for treating anorexiain a subject suffering from anorexia or the symptoms of anorexiacomprising administering to said subject an effective amount ofsertraline L-lactate.

The present invention is also directed to methods for treating impulsedisorders such as trichotillomania, pathological gambling, kleptomaniaand pyromania in a subject suffering from one of said impulse disorderscomprising administering to said subject an effective amount ofsertraline L-lactate.

The present invention is also directed to methods for treatingpremenstrual syndrome in a subject suffering from premenstrual syndromecomprising administering to said subject an effective amount ofsertraline L-lactate.

The present invention is also directed to methods for treatingonychophagia in a subject suffering from onycophagia comprisingadministering to said subject an effective amount of sertralineL-lactate.

The present invention is also directed to methods for treating psychoticdisorders of the schizophrenic type in a subject suffering from saidpsychotic disorders or suffering from such symptoms as anxiety,agitation, tension, excessive aggression, social withdrawal or emotionalwithdrawal comprising administering to said subject an effective amountof sertraline L-lactate.

The present invention is also directed to methods for treatinginflammatory disorders such as psoriasis and arthritis in a subjectsuffering from an inflammatory disorder or inflammatory disorderscomprising administering to said subject an effective amount ofsertraline L-lactate.

The present invention is also directed to methods for treatingconditions characterized by a hyperactive immune system such asrheumatoid arthritis and lupus in a subject suffering from saidconditions comprising administering to said subject an effective amountof sertraline L-lactate.

The present invention is also directed to methods for treating mentaldepression in a mentally-depressed subject comprising administering tosaid subject an effective amount of sertraline L-lactate.

The present invention is also directed to methods for treatinganxiety-related disorders such as panic disorder, generalized anxietydisorder, agoraphobia, simple phobias, social phobia, posttraumaticstress disorder, obsessive-compulsive disorder and avoidant personalitydisorder in a subject suffering from one or more of said anxiety-relateddisorders comprising administering to said subject an effective amountof sertraline L-lactate.

The present invention is particularly directed to methods for treatinganxiety-related disorders as described in the previous paragraph whereinsaid anxiety-related disorder is obsessive-compulsive disorder.

The present invention is also directed to methods for treating chemicaldependency in a subject suffering from chemical dependency comprisingadministering to said subject an effective amount of sertralineL-lactate.

The present invention is further directed to pharmaceutical compositionscomprising sertraline L-lactate and a pharmaceutically acceptablecarrier or diluent.

The present invention is still further directed to pharmaceuticalcompositions comprising sertraline L-lactate having the X-ray crystalstructure depicted in FIG. 3 and a pharmaceutically acceptable carrieror diluent

The present intention is also directed to processes for preparingsertraline L-lactate comprising reacting a salt of sertraline with abase in the presence of a suitable organic solvent to form sertralinefree base, partitioning said sertraline free base into an organicsolvent and reacting said sertraline free base with L-lactic acid in thepresence of a suitable organic solvent.

The present invention is particularly directed to processes as describedin the immediately preceding paragraph wherein said salt of sertralineis sertraline hydrochloride.

The present invention is more particularly directed to processes asdescribed in the immediately preceding paragraph wherein said solvent isethyl acetate.

The present invention is also particularly directed to processes forpreparing sertraline L-lactate comprising reacting sertraline mandelatewith a base in the presence of a suitable organic solvent to formsertraline free base, partitioning said sertraline base into an organicsolvent and reacting said sertraline free base with L-lactic acid.

The present invention is more particularly directed to processes asdescribed in the immediately preceding paragraph wherein said solvent isethyl acetate.

The present invention is further directed to processes for preparingsertraline L-lactate comprising reacting sertraline free base withL-lactic acid in the presence of a suitable organic solvent.

The present invention is particularly directed to processes as describedin the immediately-preceding paragraph wherein said solvent is ethylacetate.

The present invention is also directed to processes for preparingsertraline L-lactate comprising reacting a salt of sertraline with abase in the presence of a suitable organic solvent to form sertralinefree base, partitioning said sertraline free base into an organicsolvent and reacting said sertraline free base with L-lactic acid in thepresence of a suitable organic solvent and isolating said sertralineL-lactate from said solvent.

The present invention is also directed to sertraline L-aspartate.

The present invention is also directed to methods for treating anorexiain a subject suffering from anorexia or the symptoms of anorexiacomprising administering to said subject an effective amount ofsertraline L-aspartate.

The present invention is also directed to methods for treating impulsedisorders such as trichotillomania, pathological gambling, kleptomaniaand pyromania in a subject suffering from one of said impulse disorderscomprising administering to said subject an effective amount ofsertraline L-aspartate.

The present invention is also directed to methods for treatingonychophagia in a subject suffering from onychophagia comprisingadministering to said subject an effective amount of sertralineL-aspartate.

The present invention is also directed to methods for treatingpremenstrual syndrome in a subject suffering from premenstrual syndromecomprising administering to said subject an effective amount ofsertraline L-aspartate.

The present-invention is also directed to methods for treating psychoticdisorders of the schizophrenic type in a subject suffering from saidpsychotic disorders or suffering from such symptoms as anxiety,agitation, tension, excessive aggression, social withdrawal or emotionalwithdrawal comprising administering to said subject an effective amountof sertraline La-aspartate.

The present invention is also directed to methods for treatinginflammatory disorders such as psoriasis and arthritis in a subjectsuffering from an inflammatory disorder or inflammatory disorderscomprising administering to said subject an effective amount ofsertraline L-aspartate.

The present invention is also directed to methods for treatingconditions characterized by a hyperactive immune system such asrheumatoid arthritis and lupus in a subject suffering from saidconditions comprising administering to said subject an effective amountof sertraline L-aspartate.

The present invention is also directed to methods for treating mentaldepression in a mentally-depressed subject comprising administering tosaid subject an effective amount of sertraline L-aspartate.

The present invention is also directed to methods for treatinganxiety-related disorders such as panic disorder, generalized anxietydisorder, agoraphobia, simple phobias, social phobia, posttraumaticstress disorder, obsessive-impulsive disorder and avoidant personalitydisorder in a subject suffering from one or more of said anxiety-relateddisorders comprising administering to said subject an effective amountof sertraline L-aspartate.

The present invention is particularly directed to methods for treatinganxiety-related disorders as described in the previous paragraph whereinsaid anxiety-related disorder is obsessive-compulsive disorder.

The present invention is also directed to methods for treating chemicaldependency in a subject suffering from chemical dependency comprisingadministering to said subject an effective amount of sertralineL-aspartate.

The present invention is further directed to pharmaceutical compositionscomprising sertraline L-aspartate and a pharmaceutically acceptablecarrier or diluent.

The present invention is also directed to processes for preparingsertraline L-aspartate comprising reacting a salt of sertraline with abase in the presence of a suitable organic solvent to form sertralinefree base, partitioning said sertraline free base into an organicsolvent and reacting said sertraline free base wit aspartic acid in thepresence of a suitable organic solvent.

The present invention is particularly directed to processes as describedin the immediately preceding paragraph wherein said salt of sertralineis sertraline hydrochloride.

The present invention is more particularly directed to processes asdescribed in the immediately preceding paragraph wherein said solvent ishexane.

The present invention is further directed to processes for preparingsertraline L-aspartate comprising reacting sertraline free base withaspartic acid in the presence of a suitable organic solvent.

The present invention is particularly directed to processes as describedin the immediately preceding paragraph wherein said solvent is hexane.

The present invention is also directed to processes for preparingsertraline L-aspartate comprising reacting a salt of sertraline with abase in the presence of a suitable organic solvent to form sertralinefree base, partitioning said sertraline free base into an organicsolvent and reacting said sertraline free base with aspartic acid in thepresence of a suitable organic solvent and isolating said sertralineL-aspartate from said solvent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray crystal structure of sertraline acetate as derivedfrom single crystal X-y crystallography. (Atomic coordinates).

FIG. 2 is a characteristic X-ray diffraction pattern showing thatsertraline acetate is crystalline. (Vertical Axis: Intensity (CPS);Horizontal Axis. Two theta (degrees)).

FIG. 3 is an X-ray crystal structure of sertraline L-lactate as derivedfrom single crystal X-ray crystallography. (Atomic coordinates).

FIG. 4 is a characteristic X-Ray diffraction pattern showing thatsertraline L-lactate is crystalline. (Vertical Axis: Intensity (CPS);Horizontal Axis: Two theta (degrees)).

FIG. 5 is a characteristic X-Ray diffraction pattern showing, thatsertraline L-aspartate is crystalline. (Vertical Axis: Intensity (CPS);Horizontal Axis: Two theta (degrees)).

FIG. 6 is a PK/PD plot which presents the relationship between plasmasertraline concentration and average self-reported visual analoguescores for a nausea study presented in the Examples.

DETAILED DISCUSSION Sustained Release

The sustained-release dosage forms of this invention can be widelyimplemented. For purposes of discussion, not limitation, the manyembodiments hereunder can be grouped into classes according to designand principle of operation.

The first class of sustained release dosage forms described below ismatrix systems which include but are not limited to 1) non-erodingmatrices, tablets, multiparticulates, and hydrogel-based system; 2)hydrophilic eroding, dispersible or dissolvable matrix systems, tabletsand multiparticulates; and 3) coated matrix systems. The second classconsists of reservoir systems where release of the drug is modulated bya membrane, such as capsules, and coated tablets or multiparticulates.The third class consists of osmotic-based systems such as 1) coatedbilayer tablets; 2) coated homogeneous tablet cores; 3) coatedmultiparticulates; and 4) osmotic capsules. The fourth class consists ofswellable systems where drug is released by swelling and extrusion ofthe core components out through a passageway in a coating or surroundingshell or outer layer.

A first class includes matrix systems, in which sertraline is dissolved,embedded or dispersed in a matrix of another material that serves toretard the release of sertraline into an aqueous environment (i.e., thelumenal fluid of the GI tract). When sertraline is dissolved, embeddedor dispersed in a matrix of this sort, release of the drug takes placeprincipally from the surface of the matrix. Thus the drug is releasedfrom the surface of a device which incorporates the matrix after itdiffuses trough the matrix into the surrounding fluid or when thesurface of the device dissolves or erodes, exposing the drug. In someembodiments, both mechanisms can operate simultaneously. The matrixsystems may be large, i.e., tablet sized (about 1 cm), or small (<0.3cm). The system may be unitary, it may be divided as previouslydiscussed by virtue of being composed of several sub-units (for example,several tablets-which constitute a single dose) which are administeredsubstantially simultaneously, it may consist of several small tabletswithin a capsule, or it may comprise a plurality of particles, referredto herein as a multiparticulate. A multiparticulate can have numerousformulation applications. For example, a multiparticulate may be used assmall beads or a powder for filling a capsule shell, it may becompressed into a tablet, or it may be used per se for mixing with food(for example ice cream) to increase palatability, or as a sachet thatmay be dispersed in a liquid, such as fruit juice or water.

The multiplicity of variables affecting release of sertraline frommatrix devices permits abundant flexibility in the design of devices ofdifferent materials, sizes, and release times. Examples of modificationsof sertraline release profiles from the specific embodiments of theexamples within the scope of this invention are disclosed in detailbelow.

Non-eroding matrix tablets that provide sustained-release of sertralinecan be made with sertraline free base and with a wide range ofsertraline salts such as sertraline HCl, sertraline lactate, sertralineacetate and sertraline aspartate and water insoluble materials such aswaxes, cellulose, or other water insoluble polymers. Matrix materialsuseful for the manufacture of these dosage forms includemicrocrystalline cellulose such as Avicel (rid trademark of FMC Corp.,Philadelphia, Pa.), including grades of microcrystalline cellulose towhich binders such as hydroxypropyl methyl cellulose have been added,waxes such as paraffin, modified vegetable oils, carnauba wax,hydrogenated castor oil, beeswax, and the like, as well as polymers suchas cellulose, cellulose esters, cellulose ethers, poly(vinyl chloride),poly(vinyl acetate), copolymers of vinyl acetate and ethylene,polystyrene, and the like. Water soluble binders or release modifyingagents which can optionally be formulated into the matrix includewater-soluble polymers such as hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose HPMC), methyl cellulose, poly(N-vinyl-2-pyrrolidinone) (PVP), poly(ethylene oxide) (PEO), poly(vinylalcohol) (PVA), xanthan gum, carrageenan, and other such natural andsynthetic materials. In addition, materials which function asrelease-modifying agents include water-soluble materials such as sugarsor salts. Preferred water-soluble materials include lactose, sucrose,glucose, and mannitol, as well as HPC, HPMC; and PVP. In additionsolubilizing acid excipients such as malic acid, citric acid, erythorbicacid, ascorbic acid, adipic acid, glutamic acid, maleic acid, aconiticacid, and aspartic acid and solubilizing excipients such as partialglycerides, glycerides, glyceride derivatives, polyethylene glycolesters, polypropylene glycol esters, polyhydric alcohol esters,polyoxyethylene ethers, sorbitan esters, polyoxyethylene sorbitanesters, saccharide esters, phospholipids, polyethyleneoxide-polypropylene oxide block co-polymers, and polyethylene glycols,can be incorporated into matrix tables to increase the release rate ofsertraline, increase the total quantity of sertraline released, andpotentially increase absorption and consequently the bioavailability ofsertraline, particularly from matrix formulations that releasesertraline over a period of six hours or longer.

In addition to components of the matrix system, the size of the matrixsystem can affect the rate of sertraline release, therefore, a largematrix system such as a tablet will, in general, have a differentcomposition from a small one such as a multiparticulate to achievesimilar release profiles. The effect of the size of the matrix system onthe kinetics of sertraline release follows scaling behavior well knownin the study of diffusion. By way of illustration, the following tableshows the difussion coefficient of sertraline through the matrixrequired to achieve a characteristic time for release of 10 hours formatrix systems of different sizes that release sertraline by adiffusive-based mechanism (rather than an eroding or in combination withan eroding mechanism).

radius (cm) diffusion coefficient (cm²/s) 0.0025 (50 μm diameter) 1.7 ×10⁻¹⁰  0.1 (2 mm diameter) 3 × 10⁻⁷ 0.5 (1 cm diameter) 7 × 10⁻⁶

The above table illustrates that diffusion-coefficients necessary toachieve the target characteristic time of release can change by ordersof magnitude as the desired size of the device changes. Matrix materialswhich may be used to provide a sertraline diffusion coefficient at thelow end of the diffusion coefficient scale are polymers such ascellulose acetate. Conversely, materials at the upper end of the scaleare materials such as polymers which form hydrogels when hydrated. Therate of diffusion for any particular device can accordingly be tailoredby the material or materials selected, and the structure of the matrix.

For purposes of further illustration, to obtain a sustained-releasenon-eroding matrix in a particle of about 50 μm in diameter, a matrixmaterial of a polymer such as cellulose acetate or a similar materialwill likely be required, the slow diffusing matrix material tending tooffset the short distances characteristic of small particle size. Bycontrast in order to obtain sustained-release in a large (e.g., 1 cm)device, a material which is more liquid-like (e.g., a hydrogel, seebelow) or with greater porosity will likely be red. For devices of anintermediate size, e.g., about 1 mm in diameter, a matrix composition ofintermediate characteristics can be employed.

It is also noted tat the effective diffusion coefficient of sertralinein a matrix may be increased to the desired value by the addition ofplasticizers, pores, or pore-inducing additives, as known in the artSlow-hydrating materials may also be used to effectively reduce thediffusion rates of sertraline, particularly at times shortly afteradministration. In addition to changing the effective diffusioncoefficient, the release rate can also be altered by the inclusion ofmore soluble salt forms (relative to the free base) such as sertralinelactate, sertraline acetate, or sertraline aspartate, or excipients suchas acids and/or surfactant-like compounds that solubilize sertraline andminimize gelation, particularly in the presence of chloride ions.

A further sustained release non-eroding matrix-system comprisessertraline dispersed in a hydrogel matrix. This embodiment differs fromthe hydrophilic matrix tablet discussed below in that the hydrogel ofthis embodiment is not a compressed tablet of soluble or erodiblegranular material, but rather a monolithic polymer network. As known inthe art, a hydrogel is a water-swellable network polymer. Hydrogels canbe made in many geometries, such as caplets, tablets, andmultiparticulates. As an example, tablets can be prepared by standardtechniques containing 10 to 80% of a crosslinkable polymer. Once tabletsare formed the polymer can be crosslinked via a chemical crosslinkingagent such as gluteraldehyde or via UV irradiation forming a hydrogelmatrix. Hydrogels are preferred materials for matrix devices becausethey can absorb or be made to contain a large volume fraction of water,thereby permitting diffusion of solvated drug within the matrix.Diffusion coefficients of drugs in hydrogels are characteristicallyhigh, and for highly water-swollen gels, the diffusion coefficient ofthe drug in the gel may approach the value impure water. This highdiffusion coefficient permits practical release rates from relativelylarge devices (i.e., it is not necessary to form microparticles).Although hydrogel devices can be prepared, loaded with sertraline,stored, dispensed and dosed in the fully hydrated state, it is preferredthat they be stored, dispensed, and dosed in a dry state. In addition tostability and convenience, dry state dosing of hydrogel devices canprovide good sertraline release kinetics due to Case II transport (i.e.combination of swelling of hydrogel and diffusion of drug out throughthe swollen hydrogel). Preferred materials for forming hydrogels includehydrophilic vinyl and acrylic polymers, polysaccharides such as calciumalginate, and poly(ethylene oxide). Especially preferred arepoly(2-hydroxyethyl methacrylate), poly(acrylic acid), poly(methacrylicacid, poly(N-vinyl-2-pyrolidinone), poly(vinyl alcohol) and theircopolymers with each other and with hydrophobic monomers such as methylmethacrylate, vinyl acetate, and the like. Also preferred arehydrophilic polyurethanes containing large poly(ethylene oxide) blocks.Other preferred materials include hydrogels comprising interpenetratingnetworks of polymers, which may be formed by addition or by condensationpolymerization, the components of which may comprise hydrophilic andhydrophobic monomers such as those just enumerated.

Non-eroding matrix tablets can be made by tabletting methods common inthe pharmaceutical industry. Preferred embodiments of non-eroding matrixtablets contain 10 to 80%/ sertraline, 5 to 50% insoluble matrixmaterials such as cellulose, cellulose acetate, or ethylcellulose, andoptionally 5 to 85% plasticizers, pore formers or solubilizingexcipients, and optionally about 0.25 to 2% of a tabletting lubricant,such as magnesium stearate, sodium stearyl fumarate, zinc stearate,calcium stearate, stearic acid, polyethyleneglycol-8000, talc, ormixtures of magnesium stearate with sodium lauryl sulfate. Thesematerials can be blended, granulated, and tabletted using a variety ofequipment common to the pharmaceutical industry.

A non-eroding matrix multiparticulate comprises a plurality ofsertraline-containing particles, each particle comprising a mixture ofsertraline with one or more excipients selected to form a matrix capableof limiting the dissolution rate of the sertraline into an aqueousmedium. The matrix materials useful for this embodiment are generallywater-insoluble materials such as waxes, cellulose, or otherwater-insoluble polymers. If needed, the matrix materials may optionallybe formulated with water-soluble materials which can be used as bindersor as permeability-modifying agents. Matrix materials useful for themanufacture of these dosage forms include microcrystalline cellulosesuch as Avicel (registered trademark of FMC Corp., Philadelphia, Pa.),including grades of microcrystalline cellulose to which binders such ashydroxypropyl methyl cellulose have been added, waxes such as paraffin,modified vegetable oils, carnauba wax, hydrogenated castor oil, beeswax,and the like, as well as synthetic polymers such as poly(vinylchloride), poly(vinyl acetate), copolymer of vinyl acetate and ethylene,polystyrene, and the like. Water soluble release modifying agents whichcan optionally be formulated into the matrix include water-solublepolymers such as HPC, HPMC, methyl cellulose, PVP, PEO, PVA, xanthangum, carrageenan, and other such natural and synthetic materials. Inaddition, materials which function as release-modifying agents includewater-soluble materials such as sugars or salts. Preferred water-solublematerials include lactose, sucrose, glucose, and mannitol, as well asHPC, HPMC, and PVP. In addition any of the solubilizing acid orsurfactant type excipients previously mentioned can be incorporated intomatrix multiparticulates to increase the release rate of sertraline,increase the total quantity of sertraline released, and potentiallyincrease absorption and consequently the bioavailability of sertraline,particularly from matrix formulations that release sertraline over aperiod of six hours or longer.

A preferred process for manufacturing matrix multiparticulates is theextrusion/spheronization process. For this process, the sertraline iswet-massed with a binder, extruded through a perforated plate or die,and placed on a rotating disks The extrudate ideally breaks into pieceswhich are rounded into spheres, spheroids, or rounded rods on therotating plate. A preferred process and composition for this methodinvolves using water to wet-mass a blend comprising about 20 to 75% ofmicrocrystalline cellulose blended with, correspondingly, about 80 to25% sertraline.

A preferred process for manufacturing matrix multiparticulates is therotary granulation process. For this process sertraline and excipientssuch as microcrystalline cellulose are placed in a rotor bow in a fluidbed processor. The drug and excipient are fluidized, while spraying asolution that binds the drug and excipients together in granules ormultiparticulates. The solution sprayed into the fluid bed can be wateror aqueous solutions or suspensions of binding agents such aspolyvynylpyrrolidone or hydroxypropylmethylcellulose. A preferredcomposition for this method can comprise 10 to 80% sertraline, 10 to 60%microcrystalline cellulose, and 0 to 25% binding agent.

A further preferred process for manufacturing matrix multiparticulatesinvolves coating sertraline, matrix-forming excipients and if desiredrelease-modifying or solubilizing excipients onto seed cores such assugar seed cores known as non-pareils. Such coatings can be applied bymany methods known in the pharmaceutical industry, such as spray-coatingin a fluid bed coater, spray-drying, and granulation methods such asfluid bed or rotary granulation. Coatings can be applied from aqueous,organic or melt solutions or suspensions.

A further preferred process for manufacturing matrix multiparticulatesis the preparation of wax granules. In this process, a desired amount ofsertraline is stirred with liquid wax to form a homogeneous mixture,cooled and then forced through a screen to form granules. Preferredmatrix materials are waxy substances. Especially preferred arehydrogenated castor oil and carnauba wax and stearyl alcohol.

A further preferred process for manufacturing matrix multiparticulatesinvolves using an organic solvent to aid mixing of the sertraline withthe matrix material. This technique can be used when it is desired toutilize a matrix material with an unsuitably high melting point that, ifthe material were employed in a molten state, would cause decompositionof the drug or of the matrix material, or would result in anunacceptable melt viscosity, thereby preventing mixing of sertralinewith the matrix material. Sertraline and matrix material may be combinedwith a modest amount of solvent to form a paste, and then forced througha screen to form granules from which the solvent is then removed.Alternatively, sertraline and matrix material may be combined withenough solvent to completely dissolve the matrix material and theresulting solution (which may contain solid drug particles) spray driedto form the particulate dosage-form. This technique is preferred whenthe matrix material is a high-molecular weight synthetic polymer such asa cellulose ether or cellulose ester. Solvents typically employed forthe process include acetone, ethanol, isopropanol, ethyl acetate, andmixtures of two or more.

A further process for manufacturing matrix multiparticulates involvesusing an aqueous solution or suspension of sertraline and matrix formingmaterials. The solution or suspension can be spray dried or sprayed ordripped into a quench bath or through a light chamber to initiatecrosslinking of matrix materials and solidify the droplets. In thismanner matrices can be made from latexes (e.g. dispersed ethylcellulosewith a plasticizer such as oleic acid or with a volatile water misciblesolvent such as acetone or ethanol) by spray-drying techniques. Matricescan also be made in this manner by crosslinking a water soluble polymeror gum. For example, sodium alginate can be crosslinked by spraying intoa solution containing soluble calcium salts, polyvinyl alcohol can becrosslinked by spraying into a solution containing gluteraldehyde, anddi- and tri-acrylates can be crosslinked by UV irradiation.

Once formed, sertraline matrix multiparticulates may be blended withcompressible excipients such as lactose, microcrystalline cellulose,dicalcium phosphate, and the like and the blend compressed to form atablet. Disintegrants such as sodium starch glycolate or crosslinkedpoly(vinyl pyrrolidone) are also usefully employed. Tablets prepared bythis method disintegrate when placed in an aqueous medium (such as theGI tract), thereby exposing the multiparticulate matrix which releasessertraline therefrom. Sertraline matrix multiparticulates may also befilled into capsules, such as hard gelatin capsules.

A further embodiment of a matrix system has the form of a hydrophilicmatrix tablet that eventually dissolves or disperses in water containingsertraline and an amount of hydrophilic polymer sufficient to provide auseful degree of control over the release of sertraline. Sertraline canbe released from such matrices by diffusion, erosion or dissolution ofthe matrix, or a combination of these mechanisms. Hydrophilic polymersuseful for forming a hydrophilic matrix include HPMC, HPC, hydroxy ethylcellulose (HEC), PEO, PVA, xanthan gum; carbomer, carrageenan, andzooglan. A preferred material is HPMC. Other similar hydrophilicpolymers may also be employed. In use, the hydrophilic material isswollen by, and eventually dissolves or disperses in, water. Thesertraline release rate from hydrophilic matrix formulations may becontrolled by the amount and molecular weight of hydrophilic polymeremployed. In general, using a greater amount of the hydrophilic polymerdecreases the release rate, as does using a higher molecular weightpolymer. Using a lower molecular weight polymer increases the releaserate. The release rate may also be controlled by the use ofwater-soluble additives such as sugars, salts, or soluble polymers.Examples of these additives are sugars such as lactose, sucrose, ormannitol, salts such as NaCl, KCl, NaHCO₃, and water soluble polymerssuch as PVP, low molecular weight HPC or HMPC or methyl cellulose. Ingeneral increasing the fraction of soluble material in the formulationincreases the release rate. In addition any of the solubilizing acidexcipients previously mentioned can be incorporated into matrix tabletsto increase the release rate of sertraline, increase the total quantityof sertraline released, and potentially increase absorption andconsequently the bioavailability of sertraline, particularly from matrixformulations that release sertraline over a period of six hours orlonger. A hydrophilic matrix tablet typically comprises about 10 to 90%by weight of sertraline and about 80 to 10% by weight of polymer.

A preferred hydrophilic matrix tablet comprises, by weight, about 30% toabout 80% sertraline, about 5% to about 35% HPMC, 0% to about 35%lactose, 0% to about 15% PVP, 0% to about 20% microcrystallinecellulose, and about 0.25% to about 2% magnesium stearate.

Mixtures of polymers and/or gums can also be utilized to makehydrophilic matrix systems. For example, homopolysaccharide gums such asgalactomannans (e.g. locust bean gum or guar gum) mixed withheteropolyoaccharide gums (e.g. xanthan gum or its derivatives) canprovide a synergistic effect at in operation provides faster forming andmore rigid matrices for the release of active agent (as disclosed inU.S. Pat Nos. 5,455,046 and 5,512,297). Optionally, crosslinking agentssuch as calcium salts can be added to improve matrix properties.

Hydrophilic matrix formulations that eventually dissolve or disperse canalso be made in the form of multiparticulates. Hydrophilic matrixmultiparticulates can be manufactured by the techniques describedpreviously for non-eroding matrix multiparticulates. Preferred methodsof manufacture are layering sertraline, a hydrophilic matrix material,and if desired release modifying agents onto sugar seed cores (e.g.non-pareils) via a spray-coating process or to form multiparticulates bygranulation, such as in a rotary granulation of sertraline, hydrophilicmatrix material, and if desired release modifying agents.

The matrix systems as a class often exhibit non-constant release of thedrug from the matrix. This result may be a consequence of the diffusivemechanism of drug release, and modifications to the geometry of thedosage form and/or coating or partially coating the dosage form can beused to advantage to make the release rate of the drug more constant asdetailed below.

In a further embodiment, a sertraline matrix tablet is coated with animpermeable coating, and an orifice (for example, a circular hole or arectangular opening) is provided by which the content of the tablet isexposed to the aqueous GI tract. These embodiments are along the linesof those presented in U.S. Pat. No. 4,792,448 to Ranade, and asdescribed by Hansson et al., J. Pharm. Sci. 77 (1988) 322-324 hereinincorporated by reference. The opening is typically of a size such thatthe area of the exposed underlying sertraline composition constitutesless than about 40% of the surface area of the device, preferably lessthan about 15%.

In another embodiment, a sertraline matrix tablet is coated with animpermeable material on part of its surface, e.g. on one or both tabletfaces, or on the tablet radial surface.

In another embodiment, a sertraline matrix tablet is coated with animpermeable material and an opening for drug transport produced bydrilling a hole through the coating. The hole may be through the coatingonly, or may extend as a passageway into the tablet.

In another embodiment, a sertraline matrix tablet is coated with animpermeable material and a passageway for drug transport produced bydrilling a passageway through the entire tablet.

In another embodiment, a sertraline matrix tablet is coated with animpermeable material and one or more passageways for drug transport areproduced by removing one or more strips from the impermeable coating orby cutting one or more slits through the coating, preferably on theradial surface or land of the tablet.

In another embodiment, a sertraline matrix tablet is shaped in the formof a cone and completely coated with an impermeable material. Apassageway for drug transport is produced by cutting off the tip of thecone.

In another embodiment, a sertraline matrix tablet is shaped in the formof a hemisphere and completely coated with an impermeable material. Apassageway for drug transport is produced by drilling a hole in thecenter of the flat face of the hemisphere.

In another embodiment, a sertraline matrix tablet is shaped in the formof a half-cylinder and completely coated with an impermeable material. Apassageway for drug transport is produced by cutting a slit through (orremoving a strip from) the impermeable coating along the axis of thehalf-cylinder along the centerline of the flat face of thehalf-cylinder.

Those skilled in the art will appreciate that the geometricmodifications to the embodiments described above can be equivalentlyproduced by more than one method. For example, cutting or drilling tomake a passageway for drug transport can be achieved by other operationssuch as by a technique which produces the desired partial coatingdirectly.

By “impermeable material” is meant a material having sufficientthickness and impermeability to sertraline such that the majority ofsertraline is released through the passageway rather than the“impermeable material” during the time scale of the intended drugrelease (i.e., several hours to about a day). Such a coating can beobtained by selecting a coating material with a sufficiently lowdiffusion coefficient for sertraline and applying it sufficientlythickly. Materials for forming the impermeable coating of theseembodiments include substantially all materials in which the diffusioncoefficient of sertraline is less than about 10⁻⁷ cm²/s. It is notedthat the preceding diffusion coefficient can be amply sufficient toallow release of sertraline from a matrix device, as discussed above.However, for a device of the type now under discussion which has beenprovided with a macroscopic opening or passageway, a material with thisdiffusion coefficient is effectively impermeable to sertraline relativeto sertraline transport through the passageway. Preferred coatingmaterials include film-forming polymers and waxes. Especially preferredare thermoplastic polymers, such as poly(ethylene-co-vinyl acetate),poly(vinyl chloride), ethylcellulose, and cellulose acetate. Thesematerials exhibit the desired low permeation rate of sertraline whenapplied as coatings of thickness greater than about 100 μm.

A second class of sertraline sustained-release dosage forms of thisinvention includes membrane-moderated or reservoir systems such asmembrane-coated diffusion-based capsule, tablet, or multiparticulate.Capsules, tablets and multiparticulates can all be reservoir systems,such as membrane-coated diffusion-based. In this class, a reservoir ofsertraline is surrounded by a rate-limiting membrane. The sertralinetraverses the membrane by mass transport mechanisms well known in theart, including but not limited to dissolution in the membrane followedby diffusion across the membrane or diffusion through liquid-filledpores within the membrane. These individual reservoir system dosageforms may be large, as in the case of a tablet containing a single largereservoir, or multiparticulate, as in the case of a capsule containing aplurality of reservoir particles, each individually coated with amembrane. The coating can be non-porous, yet permeable to sertraline(for example sertraline may diffuse directly through the membrane), orit may be porous.

Sustained release coatings as known in the art may be employed tofabricate the membrane, especially polymer coatings, such as a celluloseester or ether, an acrylic polymer, or a mixture of polymers. Preferredmaterials include ethyl cellulose, cellulose acetate and celluloseacetate butyrate. The polymer may be applied as a solution in an organicsolvent or as an aqueous dispersion or latex. The coating operation maybe conducted in standard equipment such as a fluid bed coater, a Wurstercoater, or a rotary bed coater.

If desired, the permeability of the coating may be adjusted by blendingof two or more materials. A particularly useful process for tailoringthe porosity of the coating comprises adding a pre-determined amount ofa finely-divided water-soluble material, such as sugars or salts orwater-soluble polymers to a solution or dispersion (e.g., an aqueouslatex) of the membrane-forming polymer to be used. When the dosage formis ingested into the aqueous medium of the GI tract, these water solublemembrane additives are leached out of the membrane, leaving pores whichfacilitate release of the drug. The membrane coating can also bemodified by the addition of plasticizers, as known in the art.

A particularly useful variation of the process for applying a membranecoating comprises dissolving the coating polymer in a mixture ofsolvents chosen such that as the coating dries, a phase inversion takesplace in the applied coating solution, resulting in a membrane with aporous structure. Numerous examples of this type of coating system aregiven in European Patent Specification 0 357 369 B1, published Mar. 7,1990, herein incorporated by reference.

The morphology of the membrane is not of critical importance so long asthe permeability characteristics enumerated herein are met. However,specific membrane designs will have membrane morphology constraints inorder to achieve the desired permeability. The membrane can be amorphousor crystalline. It can have any category of morphology produced by anyparticular process and can be, for example, an interfacially-polymerizedmembrane (which comprises a thin rate-limiting skin on a poroussupport), a porous hydrophilic membrane, a porous hydrophobic membrane,a hydrogel membrane, an ionic membrane, and other such membrane designswhich are characterized by controlled permeability to sertraline.

A useful reservoir system embodiment is a capsule having a shellcomprising the material of the rate-limiting membrane, including any ofthe membrane materials previously discussed, and filled with asertraline drug composition. A particular advantage of thisconfiguration is that the capsule may be prepared independently of thedrug composition, thus process conditions that would adversely affectthe drug can be used to prepare the capsule. A preferred embodiment is acapsule having a shell made of a porous or a permeable polymer made by athermal forming process. An especially preferred embodiment is a capsuleshell in the form of an asymmetric membrane; i.e., a membrane that has athin dense region on one surface and most of whose thickness isconstituted of a highly permeable porous material. A preferred processfor preparation of asymmetric membrane capsules comprises a solventexchange phase inversion, wherein a solution of polymer, coated on acapsule-shaped mold, is induced to phase by exchanging the solvent witha miscible non-solvent. Examples of asymmetric membranes useful in thisinvention are disclosed in the aforementioned European PatentSpecification 0 357 369 B1.

Tablets can also be reservoir systems. Tablet cores containingsertraline can be made by a variety of techniques standard in thepharmaceutical industry. These cores can be coated with arate-controlling coating as described above, which allows the sertralinein the reservoir (tablet core) to diffuse out through the coating at thedesired rate.

Another embodiment of reservoir systems comprises a multiparticulatewherein each particle is coated with a polymer designed to yieldsustained release of sertraline. The multiparticulate particles eachcomprise sertraline and one or more excipients as needed for fabricationand performance. The size of individual particles, as previouslymentioned, is generally between about 50 μm and about 3 mm, althoughbeads of a size outside this-range may also be useful. In general, thebeads comprise sertraline and one or more binders. As it is generallydesirable to produce dosage forms which are small and easy to swallow,beads which contain a high fraction of sertraline relative to excipientsare preferred. Binders useful in fabrication of these beads includemicrocrystalline cellulose (e.g., Avicel®, FMC Corp.), HPC, HPMC, andrelated materials or combinations thereof. In general, binders which areuseful in granulation and tabletting, such as starch, pregelatinizedstarch, and PVP may also be used to form multiparticulates.

Reservoir system sertraline multiparticulates may be prepared usingtechniques known to those skilled in the art, including, but not limitedto, the techniques of extrusion and spheronization, wet granulation,fluid bed granulation, and rotary bed granulation. In addition, thebeads may also be prepared by building the sertraline composition (drugplus excipients) up on a seed core (such as a non-pareil seed) by adrug-layering technique such as powder coating or by applying thesertraline composition by spraying a solution or dispersion ofsertraline in an appropriate binder solution onto seed cores in afluidized bed such as a Wurster coater or a rotary processor. An exampleof a suitable composition and method is to spray a dispersion of asertraline/hydroxypropylcellulose composition in water. Advantageously,sertraline can be loaded in the aqueous composition beyond itssolubility limit in water.

A preferred method for manufacturing the multiparticulate cores of thisembodiment is the extrusion/spheronization process, as previouslydiscussed for matrix multiparticulates. A preferred process andcomposition for this method involves using water to wet-mass a blend ofabout 5 to 75% of microcrystalline cellulose with correspondingly about95 to 25% sertraline. Especially preferred is the use of about 5-30%microcrystalline cellulose with correspondingly about 95-70% sertraline.

A preferred process for making multiparticulate cores of this embodimentis the rotary-granulation process, as previously discussed for matrixmultiparticulates.

A preferred process for making multiparticulate cores of this embodimentis the process of coating seed cores with sertraline and optionallyother excipients, as previously discussed for matrix multiparticulates.

A sustained release coating as known in the art, especially polymercoatings, may be employed to fabricate the membrane, as previouslydiscussed for reservoir systems. Suitable and preferred polymer coatingmaterials, equipment, and coating methods also include those previouslydiscussed.

The rate of sertraline release from the coated multiparticulates canalso be controlled by factors such as the composition and binder contentof the drug-containing core, the thickness and permeability of thecoating, and the surface-to-volume ratio of the multiparticulates. Itwill be appreciated by those skilled in the art that increasing thethickness of the coating will decrease the release rate, whereasincreasing the permeability of the coating or the surface-to-volumeratio of the multiparticulates will increase the release rate. Ifdesired, the permeability of the coating may be adjusted by blending oftwo or more materials. A useful series of coatings comprises mires ofwater-insoluble and water-soluble polymers, for example, ethylcelluloseand hydroxypropyl methylcellulose, respectively. A particularly usefulmodification to the coating is the addition of finely-dividedwater-soluble material, such as sugars or salts. When placed in anaqueous medium, these water soluble membrane additives are leached outof the membrane, leaving pores which facilitate delivery of the drug.The membrane coating may also be modified by the addition ofplasticizers, as is known to those skilled in the art. A particularlyuseful variation of the membrane coating utilizes a mixture of solventschosen such that as the coating dries, a phase inversion takes place inthe applied coating solution, resulting in a membrane with a porousstructure.

A preferred embodiment is a multiparticulate with cores comprising about50 to 95% sertraline and 5 to 50% of one or more of the following:microcrystalline cellulose, PVP, HPC and HPMC. The individualcores-are-coated with either an aqueous dispersion of ethyl cellulose,which dries to form a continuous film, or a film of cellulose acetatecontaining PEG, sorbitol or glycerol as a release-modifying agent.

A third class of sertraline sustained-release dosage forms includes theosmotic delivery devices or “osmotic pumps” as they are known in theart. Osmotic pumps comprise a core containing an osmotically effectivecomposition surrounded by a semipermeable membrane. The term“semipermeable” in this context means that water can pass through themembrane, but solutes dissolved in water permeate through the membraneat a rate significantly slower than water. In use, when placed in anaqueous environment, the device imbibes water due to the osmoticactivity of the core composition. Owing to the semipermeable nature ofthe surrounding membrane, the contents of the device (including the drugand any excipients) cannot pass through the non-porous regions of themembrane and are driven by osmotic pressure to leave the device throughan opening or passageway pre-manufactured into the dosage form or,alternatively, formed in situ in the GI tract as by the bursting ofintentionally-incorporated weak points in the coating under theinfluence of osmotic pressure, or alternatively, formed in situ in theGI tract by dissolution and removal of water-soluble porosigensincorporated in the coating. The osmotically effective compositionincludes water-soluble species, which generate a colloidal osmoticpressure, and water-swellable polymers. The drug itself (if highlywater-soluble) may be an osmotically effective component of the mixture.Sertraline acetate and lactate, having solubilities of 65 and 125 mg/ml,respectively, can provide an osmotic pressure in the me 2-4 atmospheres,enough to contribute some osmotic driving force. Because sertraline is abase, its solubility is generally higher at acidic pH. Therefore, theosmotic effectiveness of sertraline is aided by presence of acidicbuffers in t formulation. The drug composition may be separated from theosmotically effective components by a movable partition or piston.

Materials useful for forming the semipermeable membrane includepolyamides, polyesters, and cellulose derivatives. Preferred arecellulose ethers and esters. Especially preferred are cellulose acetate,cellulose acetate butyrate, and ethyl cellulose. Especially usefulmaterials include those which spontaneously form one or more exitpassageways, either during manufacturing or when placed in anenvironment of use. These preferred materials comprise porous polymers,the pores of which are formed by phase inversion during manufacturing,as described below, or by dissolution of a water-soluble componentpresent in the membrane.

A class of materials which have particular utility for formingsemipermeable membranes for use in osmotic delivery devices is that ofporous hydrophobic polymers or vapor-permeable films, as disclosed bycommonly assigned co-pending U.S. application Serial No. 08/096,144filed Jul. 22, 1993 abandoned, herein incorporated by reference. Thesematerials are highly permeable-to water, but highly impermeable tosolutes dissolved in water. These materials owe their high waterpermeability to the presence of numerous microscopic pores (i.e., poreswhich are much larger than molecular dimensions). Despite theirporosity, these materials are impermeable to molecules in aqueoussolution because liquid water-does not wet the pores. Water in the vaporphase is easily able to pass across membranes made from these materials.Such membranes are also known as vapor permeable membranes.

A preferred embodiment of this class of osmotic delivery devicesconsists of a coated bi-layer tablet. The coating of such a tabletcomprises a membrane permeable to water but substantially impermeable tosertraline and excipients contained within. The coating contains one ormore exit passageways in communication with the sertraline-containinglayer for delivering the drug composition. The tablet core consists oftwo layers: one layer containing the sertraline composition (includingoptional osmagents and hydrophilic water-soluble polymers) and anotherlayer consisting of an expandable hydrogel, with or without additionalosmotic agents. This type of delivery device is illustrated in Example20.

When placed in an aqueous medium, the tablet imbibes water through themembrane, causing the sertraline composition to form a dispensibleaqueous composition, and causing the hydrogel layer to expand and pushagainst the sertraline composition, forcing the sertraline compositionout of the exit passageway. The sertraline composition can swell aidingin forcing the sertraline out the passageway. Sertraline can bedelivered from this type of delivery system either dissolved ordispersed in the composition forced out of the exit passageway.

The rate of sertraline delivery is controlled by such factors as thepermeability and thickness of the coating, the osmotic pressure of thesertraline-containing layer, the water activity of the hydrogel layer,and the surface area of the device. Those skilled in the art willappreciate that increasing the thickness of the coating will reduce therelease rate, whereas increasing the permeability of the coating or thewater activity of the hydrogel layer or the osmotic pressure of thesertraline-containing layer or the surface area of the device willincrease the release rate.

Exemplary materials which are useful to form the sertraline composition,in addition to the sertraline itself, include HPMC, PEO, and PVP, andother pharmaceutically-acceptable carriers. In addition, osmagents suchas sugars or salts, especially sucrose, mannitol, or sodium chloride,may be added. Materials which are useful for forming the hydrogel layerinclude sodium carboxymethyl cellulose, poly (ethylene oxide),poly(acrylic acid), sodium (poly-acrylate) and other highmolecular-weight hydrophilic materials. In addition, osmagents such assugars or salts may be added. Particularly useful are poly (ethyleneoxide)s having a molecular weight from about 5,000,000 to about7,500,000.

Materials which are useful for forming the coating are cellulose esters,cellulose ethers, and cellulose ester-ethers. Preferred are celluloseacetate and ethylceollulose and optionally with PEG included aspermeability modifying component.

The exit passageway must be located on the side of the tablet containingthe sertraline composition. There may be more than one such exitpassageway. The exit passageway may be produced by mechanical means orby laser drilling, or by creating a difficult-to-coat region on thetablet by use of special tooling during tablet compression or by othermeans. The rate of sertraline delivery from the device may be optimizedso as to provide a method of delivering sertraline to a mammal foroptimum therapeutic effect.

Osmotic systems can also be made with a homogeneous core surrounded by asemipermeable membrane coating. As illustrated in Examples 16, 17, and18, sertraline can be incorporated into a tablet core that also containsother excipients that provide sufficient osmotic driving force andoptionally solubilizing excipients such as acids or surfactant-typecompounds. A semipermeable membrane coating can be applied viaconventional tablet-coating techniques such as using a pan coater. Adrug-delivery passageway can then be formed in this coating by drillinga hole in the coating, either by use of a laser or other mechanicalmeans. Alternatively, the passageway may be formed by rupturing aportion of the coating or by creating a region on the tablet that isdifficult to coat, as described above.

An embodiment of sertraline-sustained-release osmotic dosage forms ofthis invention comprises an osmotic sertraline containing tablet, whichis surrounded by an asymmetric membrane, where said asymmetric membranepossesses one or more thin dense regions in addition to less denseporous regions. This type of membrane, similar to those used-in thereverse-osmosis industry, generally allows higher osmotic fluxes ofwater than can be obtained with a dense membrane. When applied to a drugformulation, e.g. a tablet, an asymmetric membrane allows high drugfluxes and well-controlled sustained drug release. This asymmetricmembrane comprises a semipermeable polymeric material, that is, amaterial which is permeable to water, and substantially impermeable tosalts and organic solutes such as drugs (e.g. sertraline).

Materials useful for forming the semipermeable membrane includepolyamides, polyesters, and cellulose derivatives. Preferred arecellulose ethers and esters. Especially preferred are cellulose acetate,cellulose acetate butyrate and ethyl cellulose. Especially usefulmaterials include those which spontaneously form one or more exitpassageways, either during manufacturing or when placed in anenvironment of use. These preferred materials comprise porous polymers,the pores of which are formed by phase inversion during manufacturing,as described above, or by dissolution of a water-soluble componentpresent in the membrane.

The asymmetric membrane is formed by a phase-inversion process. Thecoating polymer, e.g. ethylcellulose or cellulose acetate, is dissolvedin a mixed solvent system comprising a mixture of solvents (e.g.acetone) and non-solvents (e.g. water) for the ethylcellulose orcellulose acetates. The components of the mixed solvent are chosen suchthat the solvent (e.g. acetone) is more volatile than the non-solvent(e.g. water). When a tablet is dipped into such a solution, removed anddried, the solvent component of the solvent mixture evaporates morequickly than the non-solvent. This change in solvent composition duringdrying causes a phase-inversion, resulting in precipitation of thepolymer on the tablet as a porous solid with a thin dense outer region.This outer region possesses multiple pores through which drug deliverycan occur.

In a preferred embodiment of an asymmetric membrane-coated tablet, thepolymer/solvent/non-solvent mixture is sprayed onto a bed of tablets ina tablet-coating apparatus such as a Freund HCT-60 tablet coater. Inthis process, the tablet is coated with thick porous regions, and with afinal outer thin dense region.

In the environment of use, e.g. the GI tract-water is imbibed throughthe semipermeable asymmetric membrane into the tablet core. As solublematerial in the tablet core dissolves, an osmotic pressure gradientacross toe membrane builds. When the hygrostatic pressure within themembrane enclosed core exceeds the pressure of the environment of use(e.g. the GI lumen), the sertraline-containing solution is “pumped” outof the dosage form through preformed pores in the semipermeablemembrane. The constant osmotic pressure difference across the membraneresults in a constant well-controlled delivery of sertraline to the useenvironment. A portion of the sertraline dissolved in the tablet alsoexits via diffusion.

Several illustrative formulations of this type of device are describedin examples 16, 17, 18, and 19.

In this asymmetric-membrane-coated sertraline tablet embodiment, saltsof sertraline are preferred due to their aqueous solubility. Thehydrochloride, aspartate, acetate and lactate salts are especiallypreferred. Of these, thee acetate and lactate salts are most preferred.Also preferred are the inclusion of one or more solubilizing excipients,ascorbic acid, erythorbic acid, citric acid, glutamic acid, asparticacid, partial glycerides, glycerides, glycerides derivatives,polyethylene glycol esters, polypropylene glycol esters, polyhydricalcohol esters, polyoxyethylene ethers, sorbitan esters, polyoxyethylenesorbitan esters, saccharide esters, phospholipids, polyethyleneoxide-polypropylene oxide block co-polymers, and polyethylene glycols.Most preferred are solubilizing excipients ascorbic add, aspartic acid,glyceryl monocaprylate, glyceryl monostearate, glyceryl monolaurate, andC8-C10 partial glycerides.

Osmotic tablets can also be made with a core tablet containing osmagentsand/or solubilizing excipients surrounded first by a drug containinglayer and then second a semipermeable coating. The core tabletcontaining osmagents and/or solubilizing excipients can be made bystandard tabletting methods known in the pharmaceutical industry. Thedrug containing layer may be applied around the core by spray-coatingmethods where a solution or slurry of drug and excipients is coated ontothe tablet core. The drug and excipients may also be layered around thetablet core by making a “layered” type of configuration using a tabletpress to form a second drug-containing layer around the tablet core asdescribed in Example 19. This type of compression coating method can beused to apply a powder coating (without solvents) around a tablet-core.The semipermeable coating can then be applied to the layered core bymany processes known in the art such as spray-coating or dip-coatingmethods described previously in these specifications.

Another embodiment of sustained release sertraline osmotic dosage formsof this invention consists of sertraline multiparticulates coated withan asymmetric membrane. Sertraline-containing multiparticulates areprepared by, for example, extrusion/spheronization or fluid bedgranulation, or by coating non-pareil seeds with a mixture of sertralineand a water-soluble polymer, as described above. Sertraline-containingmultiparticulates are then spray-coated with a solution of a polymer ina mixture of a solvent and a non-solvent, as described above, to formasymmetric-membrane-coated multiparticulates. This spray operation ispreferably carried out in a fluid bed coating apparatus, e.g. a GlattGPCG-5 fluid bed coater.

The polymer used for forming the semipermeable asymmetric membrane ischosen as described above for asymmetric membrane coated tablets.Likewise excipients for the multiparticulate cores can be chosen asdescribed above for asymmetric-membrane coated tablets.

Osmotic capsules can be made using the same or similar components tothose described above for osmotic tablets and multiparticulates. Thecapsule shell or portion of the capsule shell can be semipermeable andmade of materials described above. The capsule can then be filled eitherby a powder or liquid consisting of sertraline, excipients that provideosmotic potential, and optionally solubilizing excipients. The capsulecore can also be made such that it has a bilayer or multilayercomposition a to the bilayer tablet described above.

A fourth class of sertraline sustained release dosage forms of thisinvention comprises coated swellable tablets and multiparticulates, asdescribed in co-pending commonly assigned U.S. Serial No. 07/296,464,filed Jan. 12 1989 abandoned (published as EP 378404A2; Jul. 7, 1990),herein incorporated by reference. Coated swellable tablets comprise atablet core comprising sertraline and a swelling material, preferably ahydrophilic polymer, coated with a membrane which contains holes orpores trough which, in the aqueous use environment, the hydrophilicpolymer can extrude and carry out the-sertraline. Alternatively, themembrane may contain polymeric or low molecular weight water solubleporosigens which dissolve in the aqueous use environment, providingpores through which the hydrophilic polymer and sertraline may extrude.Examples of porosigens are water-soluble polymers such ashydroxypropylmethylcellulose, and low molecular weight compounds likeglycerol, sucrose, glucose, and sodium chloride. In addition, pores maybe formed in the coating by drilling holes in the coating using a laseror other mechanical means. In this fourth class of sertraline sustainedrelease dosage forms, the membrane material may comprise anyfilm-forming polymer, including polymers which are water permeable orimpermeable, providing that the membrane deposited on the tablet core isporous or contains water-soluble porosigens or possesses a macroscopichole for water ingress and sertraline release. Multiparticulates (orbeads) may be similarly prepared, with a sertraline/swellable materialcore, coated by a porous or porosigen-containing membrane. Embodimentsof this fourth class of sertraline sustained release dosage forms mayalso be multilayered, as described in EP 378 404 A2.

Sustained release formulations may also be prepared with a small portionof the dose released initially rapidly, followed by sustained release ofthe remaining majority portion of the dose. The combined sertralinerelease profile in this case is within the scope of sustained releasedosage forms of this invention, i.e. sertraline is released at a rateless ton 40 mgA/hr, provided said dosage form (1) releases not more than70% of the sertraline contained therein within the first hour followingingestion (or initiation of testing, and (2) releases sertraline at arate of at least 1 mgA/hr.

When formulating sertraline, it may be advantageous to employ a highsolubility salt, a formulation which otherwise increases sertralinesolubility, or a combination of both collectively e to as a “highsolubility form”. The following is a discussion of the reasons andadvantages accruing, from a formulations standpoint, from the use ofhigh solubility forms of sertraline. Whether due to the salt formemployed or the particular excipients employed in the dosage form, thehigh solubility form should effect a sertraline solubility of at least10 mgA/ml.

Salts of sertraline or excipients that in combination with sertralineaid in solubilizing sertraline can be beneficial to almost all types ofsustained-release dosage forms. Solubilized sertraline can enhancerelease from the dosage form by increasing the concentration gradientfor diffusive based systems such as matrix dosage forms and reservoirdosage forms. Solubilized sertraline can also enhance delivery fromosmotic dosage forms in that a more soluble sertraline can increase theosmotic pressure in the core and increase the sertraline concentrationin the fluid that is pumped or extruded out of the dosage form. Inaddition, solubilized-sertraline can benefit sustained-releaseformulations by aiding absorption of drug from the G.I. tract. Forexample, higher concentrations of drug in the colon can increaseabsorption due to a higher concentration gradient across the colonicwall.

Solubilization can be particularly important for sustained-releasesertraline formulations, since sertraline tends to form gels in manyaqueous solutions, including solutions such as the intestinal fluidswhich contain chloride ions. Sertraline gels can be formed by simplyintroducing chloride ions into solutions of sertraline lactate orsertraline acetate. Similarly gels can be formed by introducing acidssuch as tartaric acid or combinations of acids and surfactants such assuccinic acid and sodium lauryl sulfate to sertraline solutions.However, other acids and/or surfactant-like compounds can providesolubilizing effects, minimizing gel formation and providing aformulation basis for delivering sertraline in aqueous solutionscontaining chloride ions, such as intestinal fluids.

The gelling of sertraline is surprising, and the ability of certainadditives to prevent this gelling is both surprising and unpredictable.

Gelling of sertraline in sustained release dosage forms can beparticularly detrimental in non-eroding matrix systems, reservoirsystems, and osmotic systems. In each of these types of sustainedrelease formulations release of the drug is dependent on transport ofthe drug across a distance within the device (matrix or coating layer)to the surrounding fluid. This drug transport can occur by diffusive orconvective mechanisms. In both mechanisms, formation of a gel can reducetransport by an order of magnitude or more and in many cases will resultin devices that exhibit incomplete drug release (e.g., less than 70% ofthe total drug in the formulation).

Thus, it is advantageous to utilize methods to solubilize sertraline insustained release formulations. One-method of solubilizing sertraline isto make sertraline salts that have higher solubility, such as sertralinelactate, sertraline acetate, and sertraline aspartate. Preferred saltsexhibit solubilities in water that are over 3 times greater than thesertraline HCl sat, which has a solubility of about 3 mgA/ml.

Another method of solubilizing sertraline is to use an agent, referredto herein as a “solubilizing agent”, which actually functions toincrease and preferably maintain the solubility of sertraline (or a saltthereof) in a use environment relative to the solubility of sertralinein the same use environment when the solubilizing agent is not present.

Many solubilizing agents useful herein can be grouped into several broadcategories:

1. Organic acids and organic acid salts;

2. Partial Glycerides, i.e., less than fully esterified derivatives ofglycerin, including monoglycerides and diglycerides;

3. Glycerides;

4. Glyceride derivatives;

5. Polyethylene glycol esters;

6. Polypropylene glycol esters;

7. Polyhydric alcohol esters;

8. Polyoxyethylene ethers;

9. Sorbitan esters; and

10. Polyoxyethylene sorbitan esters.

11. Carbonate salts.

The amount of solubilizing agent which should be employed depends on theparticular solubilizing agent.

In the case of solubilizing agents which are organic acids the preferredamount of solubilizer can be calculated as a ratio multiplied by thequantity of sertraline to be used, wherein the ratio is of organic acidsolubility to solubility of sertraline salt (organic acid or saltsolubility/sertraline or sertraline salt solubility)×quantity ofsertraline where the solubilities referred to are in mg/ml. The aboveexpression is approximate, and some adjustment may be advantageous foroptimization. Generally the above expression will give a quantity whichis plus or minus 25% of the final value employed, although higherquantities of solubilizing agent can be incorporated without anyparticular additional advantage. In addition, organic acid salts can beadded to modify the pH and/or solubility of the organic acid,effectively optimizing the solubilization effect of the agents.

For other types of solubilizing agents listed, typically the amount ofsolubilizing agent employed in the dosage form will be 1 to 150%/ byweight of the amount of sertraline employed therein, preferably 1 to100%, more preferably 3 to 75%. Amounts of solubilizing agent higherthan 150% may be employed, although it is believed that in most cases noparticular advantage would be provided.

Examples of organic acids useful in the invention include malic, citric,erythorbic, adipic, glutamic, aspartic, maleic, aconitic, and ascorbicacid. Preferred acids are citric, erythorbic ascorbic, glutamic, andaspartic. Salts of organic acids such as alkaline earth metal(magnesium, calcium) salts and alkali metal (lithium, potassium, sodium)salts are also effective as well as mixtures of organic acids and theirsalts. Calcium salts such as calcium carbonate, calcium acetate, calciumascorbate, calcium citrate, calcium gluconate monohydrate, calciumlactobionate, calcium gluceptate, calcium levulinate, calciumpantothenate, calcium proprionate, calcium phosphate dibasic, andcalcium saccharate are preferred organic acid salts.

Examples of compounds within the other categories mentioned above aresummarized in Table 1.

TABLE 1 Solubilizing Agents Class Examples, Chemical Name Examples,Trade Designation, (Vendor) Partial Glyceryl MonocaprylateMonocaprylin ® (Sigma), Capmul ® Glycerides MCM(Abitec), Imwitor ® 308(Hüls) C8-C10 Partial Glycerides Capmul ® MCM (Abitec), Imwitor ® 742(Hüls), Imwitor ® 988 (Hüls) Glyceryl Monooleate Myverol ® 18-99(Eastman), Calgene ® GMO (Calgene), Capmul ® GMO(Abitec) GlycerylMonolinoleate Myverol ® 18-92 (Eastman) Glyceryl Monostearate Imwitor ®191 (Hüls) Calgene ® GSO(Calgene) Glyceryl Monolaurate Imwitor ® 312(Hüls) Calgene ® GLO (Calgene) Glyceryl Dilaurate Capmul ® GDL (Abitec)Glycerides Triacetin Triacetin (Sigma) Glyceride PEG-DerivitizedGlycerides Cremophor ® RH40, Cremophor ® RH60 Derivatives (BASF),Acconon ® CA5, CA-9, CA-15, W230, TGH (Abitec) Polyglycolized GlyceridesGelucire ® 44/14, 42/12, 50/13, 53/10, 35/10, 48/09, 46/07, 62/05,50/02; Labrasol ® (Gattefosse); Capmul ® 3GO; 3GS, 6G2O, 6G2S, 10G4O,10G10O (Abitec) Polyethylene PEG 200 Monolaurate, Calgene ® 20-L,Calgene ® 40-L, glycol Esters PEG 400 Monolaurate, Calgene ® 60-L PEG600 Monolaurate PEG 200 Monostearate, Calgene ® 20-S, Calgene ® 40-S,PEG 400 Monostearate, Calgene ® 60-S PEG 600 Monostearate PEG 200Dilaurate, PEG Calgene ® 22-L, Calgene ® 42-L 400 Dilaurate, PEG 600Calgene ® 62-L Dilaurate Polypropylene Propylene Glycol Captex ® 200(Abitec) Glycol Esters Dicaprylate Polyhydric Diethylene GlycolCalgene ® DGL Alcohol Esters Monolaurate Propylene Glycol Calgene ® PGMLMonolaurate Ascorbyl Palmitate Ascorbyl Palmitate (Sigma)Polyoxyethylene PEG Lauryl Ether Nonionic L-4 (Calgene) Ethers PEGStearyl Ether Nonionic S-20 (Calgene), Myrj 45, 52, 53, 59 (Sigma)Sorbitan Esters Sorbitan Monolaurate Calgene ® SML, Span ® 20 (Sigma)Sorbitan Monooleate Calgene ® SMO, Span ® 80 (Sigma) PolyoxyethylenePOE-20 Sorbitan Calgene ® PSML-20, Span ® 20(Sigma), Sorbitan EstersMonolaurate Tween ® 20 (Sigma), Capmul ® POE-L (Abitec) POE-20Monooleate Tween ® 80, PSMO-20 Saccharide Sucrose Monolaurate RyotoLW-1540 (Chem Service) Esters Phospholipids Phosphatidyl cholineLecithin (Sigma) Mixed phospholipids Emphos D70-30C (Witco) Block Co-PEO-PPO Block Pluronic ® F-68, F127, L-62 (BASF) polymers CopolymersPolyethylene PEG 3350 Various sources Glycols

In addition other compounds useful as solubilizing agents in theinvention are ethyl propionate, methyl paraben, propyl paraben, propylgaliate, niacinamide, ethyl vanillin, paraaminobenzoic acid, butylatedhydroxyanisole, imidurea, and glycine. It is also noted that preferredcompositions include mixtures of an organic acid with or without acorresponding organic acid salt, and one or more of the non-organicsolubilizers listed above or in Table 1. It is also noted that it hasgenerally been observed that in order to be most effective thesolubilizer should have a solubility in the aqueous chloride-ioncontaining use environment of at least 1 mg/ml, and preferably greaterthan 5 mg/ml.

A preferred group of solubilizing agents, in addition to the preferredorganic acids previously mentioned, includes those in Table 2.

TABLE 2 Preferred Solubilizing Agents Class Examples, Chemical NameExamples, Trade Names (source) Partial Glyceryl monocaprylateMonocaprylin (sigma), Capmul ® Glycerides MCM(Abitec), Imwitor ® 308(Hüls) C8-C10 Partial Capmul ® MCM (Abitec), Imwitor ® 742 Glycerides(Hüls), Imwitor ® 988 (Hüls) Glyceryl Monostearate Imwitor ® 191 (Hüls)Calgene ® GSO(Calgene) Glyceryl Monolaurate Imwitor ® 312 (Hüls)Calgene ® GLO (Calgene) Glycerides Triacetin Triacetin (Sigma) SorbitanEsters Sorbitan Monolaurate Calgene ® SML, Span ® 20 (Sigma) SorbitanMonooleate Calgene ® SMO, Span ® 80 (Sigma) Phospholipids Phosphatidylcholine Lecithin (Sigma) Mixed phospholipids Emphos D70-30C (Witco)Block Co- PEO-PPO Block Pluronic ® F-68, F127, L-62 (BASF) polymersCopolymers Polyethylene PEG 3350 Various sources Glycols Note:Commercial vendors shown above are as follows: Abitec Corp. Janesville,WI BASF, Parsippany, NJ Calgene Chemical Inc. Skokie, IL Chem Service,Inc., West Chester, PA Hüls America, Piscataway, NJ Sigma, St. Louis, MOWitco, Houston, Tx

Preferred combinations of solubilizing agents include (1) an organicacid plus a salt of the same or a different organic acid, (2) an organicacid plus a non-ionic solubilizing agent such as any of those listed inTable 1, and (3) an organic acid plus a salt of the same or a differentorganic acid plus a non-ionic solubilizing agent

Particularly preferred individual solubilizing agents include asparticacid, glyceryl monocaprylate, glyceryl monolaurate, calcium acetate,ascorbic acid, citric acid, glutamic acid, and calcium carbonate.Aspartic acid, glyceryl monocaprylate, and calcium acetate are mostpreferred.

Also preferred are combinations of the preferred acids and preferredsolubilizing surfactant-like compounds. A screening test useful fortesting candidate solubilizers for use together with low solubilitysertraline salts, such as sertraline hydrochloride, is set forth in theexamples.

Preferred embodiments of sustained release formulations are osmoticsystems comprising a core containing sertraline lactate or sertralineacetate or sertraline aspartate, an acid such as ascorbic, erythorbic,citric, glutamic, or aspartic acid, and if needed, a soluble sugar as anosmogent, binder material such as microcrystalline cellulose, swellablehydrophilic polymers, and a lubricant such as magnesium stearate. Morepreferred embodiments incorporate sertraline lactate or sertralineacetate.

Another preferred embodiment of sustained release formulations areosmotic systems comprising a core containing sertraline lactate orsertraline acetate, an acid such as ascorbic, erythorbic, citric,glutamic, or aspartic acid, a surfactant-like material such as partialglycerides, glycerides, sorbitan esters, phospholipids, polyethyleneoxide-polypropylene oxide block co-polymers, and polyethylene glycols,and if needed, a soluble sugar to increase the osmotic pressure withinthe core, swellable hydrophilic polymers, binder material such asmicrocrystalline cellulose, and a lubricant such as magnesium stearate.

Another preferred embodiment of sustained release formulations areosmotic systems comprising a core containing sertraline-lactate orsertraline-acetate, a surfactant-like material such as partialglycerides, glycerides, sorbitan esters, phospholipids, polyethyleneoxide-polypropylene oxide block co-polymers, and polyethylene glycols, asoluble sugar to increase the osmotic pressure within the core, and ifneeded, swellable hydrophilic polymers, binder material such asmicrocrystalline cellulose, and a lubricant such as magnesium stearate.

Preferred embodiments of sustained release formulations are osmoticsystems such as any of the three osmotic systems discussed immediatelyabove, and further coated with an asymmetric membrane coating made by aphase-inversion process. For use in these membrane systems sertralinelactate is especially preferred, as are ascorbic and aspartic acids, andpartial glycerides.

Delayed Plus Sustained Release

As it is an additional object of this invention to reduce the exposureof the upper GI tract to high concentrations of sertraline in order toalleviate certain side effects (e.g. nausea, diarrhea, andregurgitation), an additional class of dosage forms includes those formswhich incorporate a delay before the onset of sustained release ofsertraline. Such dosage forms may be described as spatially-delayed plussustained release sertraline dosage forms or temporally-delayed plussustained release sertraline dosage forms, as described above. Inprinciple, any sustained release device, including any of the numerousembodiments disclosed above, can be coated with an exterior, usuallyall-covering, coating which provides delayed release (i.e., of less than1 mgA/hr) prior to the onset of sustained release. The coating can be ofthe type which provide a temporal delay or a spatial delay.

A first embodiment can be illustrated by a tablet comprising animmediate-release core comprising sertraline coated with a first coatingof a polymeric material of the type useful for providing sustainedrelease of sertraline from the core and a second coating of the typeuseful for delaying release of drugs once the dosage form is ingested.The second coating breaks down and becomes permeable once the tablet hasleft the stomach or after a preset time. The first (inner) coating isapplied over and surrounds the tablet. The second (exterior or outer)coating is applied over and surrounds the first coating.

The tablet can be prepared by techniques well known in the art andcontains a therapeutically useful amount of sertraline plus suchexcipients as are necessary to form the tablet by such techniques. Thesecond coating is a delay coating, either spatially delayed ortemporally delayed.

The first coating may be a sustained release coating as known in theart, especially polymer coatings, to fabricate the membrane, aspreviously discussed for reservoir systems. Suitable and preferredpolymer coating materials, equipment, and coating methods also includethose previously discussed.

Materials useful for preparing the second (delay) coat on the tabletinclude polymers known in the art as enteric coatings for pH-triggereddelayed-release of pharmaceuticals. Such coatings are impermeable tosertraline at the pH of the stomach, but become permeable in the smallintestinal environment, whether by dissolving, disintegrating, orotherwise breaking down, so that sertraline can freely pass through thecoating. pH-sensitive polymers which are relatively insoluble andimpermeable at the pH of the stomach, but which are more soluble andpermeable at the pH of the small intestine and colon includepolyacrylamides, phthalate derivatives such as acid phthalates ofcarbohydrates, amylose acetate phthalate, cellulose acetate phthalate,other cellulose ester phthalates, cellulose ether phthalates,hydroxypropylcellulose phthalate, hydroxypropylethylcellulose phthalate,hydroxypropylmethylcellulose phthalate, methylcellulose phthalate,polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate,sodium cellulose acetate phthalate, starch acid phthalate,styrene-maleic acid dibutyl phthalate copolymer, cellulose acetatetrimellitate, styrene-maleic acid polyvinylacetate phthalate copolymer,styrene and maleic acid copolymers, polyacrylic add derivatives such asacrylic acid and acrylic ester copolymers, polymethacrylic acid andesters thereof, poly acrylic methacrylic acid copolymers, shellac, andvinyl acetate and crotonic add copolymers.

Preferred pH-sensitive polymers include shellac, phthalate derivatives,particularly cellulose acetate phthalate, polyvinylacetate phthalate,and hydroxypropylmethylcellulose phthalate; cellulose acetatetrimellitate; polyacrylic acid derivatives, particularly copolymerscomprising acrylic acid and at least one acrylic acid ester, polymethylmethacrylate blended with acrylic acid and acrylic ester copolymers; andvinyl acetate and crotonic acid copolymers.

A particularly preferred group of pH-sensitive polymers includescellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropylmethylcellulose phthalate, cellulose acetate trimellitate,anionic acrylic copolymers of methacrylic acid and methylmethacrylate,and copolymers comprising acrylic acid and at least one acrylic acidester.

The thickness of the delayed release coating is adjusted to give thedesired delay property. In general, thicker coatings are more resistantto erosion and, consequently, yield a longer delay. Preferred coatingsrange in thickness from about 20 μm to about 1 mm.

When ingested, the twice-coated tablet passes through the stomach, wherethe second coating prevents release of the sertraline (i.e. maintains arelease rate less than 1 mg/hr) under the acidic conditions prevalentthere. When the tablet passes out of the stomach (wherein certain sideeffects may be mediated) and into the small intestine, where the pH ishigher, the second coating erodes or dissolves according to thephysicochemical properties of the chosen material. Upon erosion ordissolution of the second coating, the first coating prevents immediateor rapid release of the sertraline and modulates the release so as toprevent the production of high concentrations, thereby minimizingside-effects.

A second embodiment of a delayed plus sustained release sertralinedosage form comprises a multiparticulate wherein each particle is dualcoated as described above for tablets, first with a polymer designed toyield sustained release of the sertraline and then coated with a polymerdesigned to delay onset of release in the environment of the GI tractwhen the dosage form is ingested. The beads contain sertraline and maycontain one or more excipients as needed for fabrication andperformance. Multiparticulates which contain a high fraction ofsertraline relative to binder are preferred. The multiparticulate may beof a composition and be fabricated by any of the techniques previouslydisclosed for multiparticulates used to make reservoir systems(including extrusion and spheronization, wet granulation, fluid bedgranulation, and rotary bed granulation, seed building, and so forth).

The sustained release coating may be applied as known in the art.Suitable and preferred polymer coating materials, equipment, and coatingmethods also include those previously discussed.

The rate of sertraline release from the sustained-release-coatedmultiparticulates (i.e., the multiparticulates before they receive thedelayed-release coating) and methods of modifying the coating are alsocontrolled by the factors previously discussed for system sertralinemultiparticulates.

The second membrane or coating for dual coated multiparticulates is adelayed-release coating which is applied over the firstsustained-release coating, as disclosed above for tablets, and may beformed from the same materials. However, it is preferred to effect asustained or controlled delivery of sertraline after the delayed-releasecoating has dissolved or eroded, therefore the benefits of thisembodiment may be realized with a proper combination of delayed-releasecharacter with sustained-release character, and the delayed-release partalone may or may not necessarily conform to standard USP entericcriteria. The thickness of the delayed-release coating is adjusted togive the desired delay property. In general, thicker coatings are moreresistant to erosion and, consequently, yield a longer delay.

A third embodiment of a delayed plus sustained release sertraline dosageform comprises eroding or non-eroding sertraline matrix cores, usuallytablets or multiparticulates, as described above, coated with a coatingwhich delays the commencement of sertraline sustained release until thecoated tablet passes from the stomach to the duodenum or more distally.Polymers useful for the delay-release coating are pH-sensitive polymersdescribed previously for coated reservoir tablets and multiparticulates.

pH-Triggered delayed plus sustained release sertraline dosage forms alsomay be formed by coating a matrix tablet or multiparticulate, or anosmotic tablet core or multiparticulate core with a single membranecomprising a mixture of a water-insoluble film-forming polymer,preferably a semipermeable polymer such as celluose acetate orethylcellulose, and a pH sensitive polymer chosen from the listpresented above. Preferred and particularly preferred pH-sensitivepolymers for this embodiment are those preferred and particularlypreferred pH-sensitive polymers described above. Preferred coatingmembranes of this embodiment comprise 10-70% pH-sensitive polymer. Ingeneral, thicker coating membranes will give a longer delay. In general,a lower pH-sensitive polymer content in the coating membrane will give alonger delay. The delay may be further controlled by incorporation, to alesser or greater degree, of water-soluble polymers such as HPMC, andlow molecular weight compounds like glycerol, sucrose, glucose, sodiumchloride, citric acid, and fumaric acid. The delay time may be increasedby choosing water-soluble membrane porosigens which have lowersolubility or slower hydration. For example, citric acid as a membranecoating porosigen, relative to fumaric acid as a membrane coatingporosigen, will cause a shorter delay, due to citric acid's highersolubility.

A fourth embodiment includes the osmotic dosage forms, as previouslydiscussed in the section relating to “Sustained Release”, but which areengineered to have a delay period longer than 15 minutes. Included inthe osmotic embodiments are bilayer tablets comprising (1) a sertralineand osmogent-containing layer, wherein the osmogent may be lactose,sucrose, an organic acid or base, a salt, or the like, (2) a secondlayer containing a swelling polymer, for example polyethyleneoxide, and(3) a polymeric coating around the entire bilayer tablet, said coatingcomprising preferably a semipermeable polymer such as cellulose acetatealong with one or more sertraline exit ports located on thesertraline-containing side of the tablet. The delay period can suitablybe engineered into the osmotic dosage form by increasing the thicknessof the membrane or by decreasing its porosity. Such a delay may havetherapeutic advantages such as decreased side effects and decreasedmetabolic interactions with co-administered drugs.

Osmotic dosage forms which are delayed plus sustained release dosageforms of this invention include sertraline-containing core tablets andmultiparticulates surrounded by a semipermeable asymmetric membrane. Thecore tablet contains sertraline, an osmotically effective solute, andoptionally acidic sertraline solubilizers, surfactant-like inhibitors ofsertraline gel formation, swelling polymers, viscosity alteringpolymers, and other common pharmaceutical excipients as needed. The drugitself, if highly water soluble, may be an osmotically effectivecomponent of the mixture. Salts of sertraline are preferred. Thehydrochloride, aspartate, acetate, and lactate salts are especiallypreferred. Of these, the acetate and lactate are most preferred.Sertraline acetate and lactate, having solubilities of 64 and 125 mg/ml,respectively, can provide an osmotic pressure in the range 2-4atmospheres, enough to contribute some osmotic driving force.

Materials useful for forming the semipermeable membrane includepolyamides, polyesters, and cellulose derivatives. Preferred arecellulose ethers and esters. Especially preferred are cellulose acetate,cellulose acetate butyrate, and ethyl cellulose. Especially usefulmaterials include those which spontaneously form one or more exitpassageways, either during manufacture or when placed in an environmentof use. These preferred materials are used to make porous coatings, thepores of which are formed by phase inversion during manufacturing, or bydissolution of a water-soluble component present in the membrane.Preparation of phase-inversion asymmetric semipermeable membranes hasbeen described above in this disclosure.

In a preferred embodiment of an asymmetric-membrane-coated tablet, apolymer/solvent/non-solvent mixture is sprayed onto a bed of tablets ina tablet-coating apparatus such as a Freund HCT-60 tablet coater. Inthis embodiment, the tablet is coated with thick porous regions, andwith a final outer thin dense region. To form a dense region that causesa delay, the spray solution is sprayed under conditions farther awayfrom the conditions causing phase inversion than would be used to makeasymmetric membrane-coated tablets without a delay period.

In the environment of use, e.g. in the GI tract, water is imbibedthrough the semipermeable asymmetric membrane into the tablet core. Assoluble material in the tablet core dissolves, an osmotic pressuregradient across the membrane builds. When the hydrostatic pressurewithin the membrane-enclosed core exceeds the pressure of theenvironment of use (e.g. the GI lumen), the sertraline-containingsolution is “pumped” out of the dosage form though the preformed poresin the semipermeable membrane.

It is preferred to include in the tablet or multiparticulate core one ormore sertraline-solubilizing excipients, including ascorbic acid,erythorbic acid, citric acid, glutamic acid, aspartic acid, partialglycerides, glycerides, glyceride derivatives, polyethylene glycolesters, polypropylene glycol esters, polyhydric alcohol esters,polyoxyethylene ethers, sorbitan esters, polyoxyethylene sorbitanesters, saccharide esters, phospholipids, polyethyleneoxide-polypropylene oxide block co-polymers, and polyethylene glycols.Most preferred are solubilizing excipients ascorbic acid, aspartic acid,glyceryl monocaprylate, glyceryl monostearate, glyceryl monolaurate, andC8-C10 partial glycerides.

The delay period may be engineered to be up to 3 hours or more byselection of the composition of the asymmetric membrane, e.g. by theselection of the ratio of membrane polymer (such as cellulose acetate orethylcellulose) to plasticizer (such as PEG-3350 or other water-solubleplasticizer). Increasing the membrane thickness or the membrane polymerto plasticizer ratio results in a longer delay time. The delay may befurther controlled by incorporation, to a lesser or greater degree, ofwater-soluble polymers such as HPMC, and low molecular weight compoundslike glycerol, sucrose, glucose, sodium chloride, citric acid, andfumaric acid. The delay time may be increased by choosing water-solublemembrane porosigens which have lower solubility or slower hydration. Forexample, citric acid as a membrane coating porosigen, relative tofumaric acid as a membrane coating porosigen, will cause a shorterdelay, due to citric acid's higher solubility. The delay time may beincreased by incorporating a lower proportion of non-solvent in thecoating solution to move slightly away from ideal phase inversionconditions. The delay time may be decreased by incorporating a largerproportion of osmotic excipients, or excipients with higher osmoticpressure, or solubilizers into the core formulation. Asymmetricmembrane-coated osmotic tablet delayed plus sustained release sertralinedosage forms of this invention are exemplified in Examples 17 and 18.

A fifth embodiment of delayed plus sustained release dosage formscomprises coated swelling hydrogel tablets and multiparticulates, asdescribed in copending commonly assigned U.S. Ser. No. 07/296,464, filedJan. 12, 1989, abandoned, (published as EP 378404 A2; Jul. 7, 1990),herein incorporated by reference. Coated swellable tablets comprise atablet core comprising sertraline and a swelling material, preferably ahydrophilic polymer, coated with a membrane which contains holes orpores through which, in the aqueous use environment, the hydrophilicpolymer can extrude and carry out the sertraline. Alternatively, themembrane may contain polymeric or low molecular weight water solubleporosigens which dissolve in the aqueous use environment, providingpores through which the hydrophilic polymer and sertraline may extrude.Examples of porosigens are water-soluble polymers such as HPMC, and lowmolecular weight compounds like glycerol, sucrose, glucose, sodiumchloride, citric acid, and fumaric acid. In addition, pores may beformed in the coating by drilling holes in the coating using a laser orother mechanical means. In this fifth embodiment of delayed plussustained release sertraline dosage forms, the membrane material maycomprise any film-forming polymer, including polymers which arewater-permeable or impermeable, provided that be membrane deposited onthe tablet core is porous or contains water-soluble porosigens, orpossesses a macroscopic hole for water ingress and sertraline release.

For coated swelling hydrogel tablets and multiparticulates, preferredswelling polymers for the core include polyethylene oxide of molecularweights from 3000 to 500,000, and carboxymethylcelluose. Preferredcoating polymers include cellulose acetate and ethylcellulose, andhydrophobic polymers such as ethylene vinyl acetate.

For coated swelling hydrogel and multiparticulates, the delay period maybe engineered to be up to 3 hours or more by selection of thecomposition of the membrane, i.e. by the selection of the ratio ofmembrane to porosigen. Increasing the membrane thickness or the membranepolymer to porosigen ratio results in a longer delay time. The delaytime may be increased by choosing water-soluble membrane porosigenswhich have lower solubility or slower hydration. For example, citricacid as a membrane coating porosigen, relative to fumaric acid as amembrane coating porosigen, will cause a shorter-delay, due to citricacid's higher solubility. The delay time may be decreased byincorporating a larger proportion of lower molecular weight (e.g. lessthan 20,000 daltons) swelling polymer into the core formulation.

A sixth embodiment is an enzyme-triggered system such as anenzyme-triggered supported liquid membrane coating of the type describedin International Application PCT/US93/07463, published as WO 94/12159 onJun. 9, 1994, herein incorporated by reference. The coating is amicroporous hydrophobic membrane possessing a hydrophobic liquidentrained within the pores of the membrane. This membrane encloses adiffusive matrix core or an osmotically active core which contributes tothe control of sertraline release after the dosage form has exited thestomach. The hydrophobic liquid is substantially impermeable to both theaqueous environment and the underlying sustained release formulation.The hydrophobic liquid is capable of change such that it becomespermeable to the aqueous environment. After ingestion of the dosage formby a mammal, sertraline release into the gastrointestinal system isdelayed until the dosage form has exited the stomach and moved into theduodenum. The entrained hydrophobic liquid undergoes change which isenzymatically catalyzed in the lumen of the small intestine, and not inthe stomach, such that the hydrophobic liquid in the delay coating poresbreaks down so the membrane becomes permeable to water and saline.Exemplary hydrophobic liquids are triglycerides, fatty anhydrides, fattyacid esters of cholesterol, hydrophobic amino acid esters, and the like.Preferred triglycerides include triolein, trycaprylin, trilaurin, oliveoil, palm oil, coconut oil, sesame seed oil, corn oil, peanut oil,soybean oil, and the like. Preferred fatty acid anhydrides includecaprylic anhydride, lauric anhydride, myristic anhydride and the like.Mixtures of hydrophobic liquids may be used. Exemplary materials for themicroporous hydrophobic support delay membrane or coating includecellulose esters, polycarbonates, polyalkenes, polystyrenes, polyvinylesters, polysiloxanes, polyacrylates and polyethers. Preferably thehydrophobic microporous membrane with entrained hydrophobic liquid isimpermeable to sertraline, until gastrointestinal enzymes have catalyzeda change in the hydrophobic oil, as described below.

In the environment of use, i.e., the small intestinal lumen, lipases andesterases degrade the aforementioned hydrophobic oils, formingsurfactant products in the pores of the microporous membrane of thisembodiment, thus producing aqueous channels through which the sertralinein the device core may exit through the microporous hydrophobic supportmembrane. Once the delay membrane becomes porous, release of thesertraline is controlled by the sustained release limitations of theunderlying device or the porosity and thickness of the poroushydrophobic coating.

In an enzyme-triggered supported liquid delay membrane as disclosedabove, hydrophobic oils may be used which are substrates for smallintestinal proteases such as trypsin, carboxypeptidase and chymotrypsin.Exemplary oils are hydrophobic esters of amino acid derivatives.

In a further embodiment of a spatially-delayed plus sustained releasesertraline dosage form, sustained release sertraline tablets, capsules,beads, or powders are coated with a coating which contains componentswhich are enzymatically degraded by enzymes in the rumen of the smallintestine, but not in the gastric lumen. The coating comprises waxes ortriglycerides of natural or synthetic origin which are solid at bodytemperature. In preferred embodiments, 2-20% of a material which isliquid at body temperature, and which is degraded by small intestinalenzymes (e.g. trypsin, chymatrypsin, elastase, lipase), is included.Suitable enzymatically-labile liquids are those described above for“enzyme triggered supported liquid membrane devices”. Preferred waxycoatings are applied at 3-20% of the weight of the uncoated sertralinetablet, capsule, bead, or powder.

In a seventh embodiment, a temporally-delayed sertraline dosage form,sustained release sertraline tablets, beads, or particles are preparedand are further coated with a water-soluble and/or water-disintegrabledelay layer. In preferred embodiments, disintegrating andnon-disintegrating sertraline matrix tablets or beads are coated with atemporal delay layer. Preferred delay coatings includehydoxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC),polyethylene oxide (PEO), and polyvinyl pyrrolidone (PVP). For tabletsthis coating may be applied in a tablet coating apparatus such as anHCT-30, HCT-60, or HCT-130 Coater; available from Freund Inc. Thetablets are coated with an aqueous solution of HPMC or other appropriatepolymer to a final coating weight of 5-50% of the final of the coatedtablet. Heavier coating weights give longer delays before the onset ofsertraline release into a use environment such as the GI lumen. Thedelay time may also be increased by incorporating small to moderatequantities of poorly water-soluble polymers, including but not limitedto ethylcellulose (EC), cellulose acetate (CA), and celluose acetatebutyrate, into the coating formulation. For example, the coatingformulation may consist of 95:5 HPMC/EC to 50:50 HPMC/EC, or 95:5HPMC/CA to 50:50 HPMC/CA. In the case of such mixed polymer coatingsystems, it may be necessary to adjust the solvent composition todissolve the mixture of water-soluble and poorly water-soluble polymers.For example, mixtures of acetone and water, or ethanol and water, may beused as needed. Beads and particles may be similarly coated using afluid bed coating apparatus, such as a Glatt GPCG-5 coater. For beads,the coating comprises from about 10% to about 100% of tee weight of theuncoated bead core. For sertraline powders, the coating comprises fromabout 15% to about 200% of the weight of the uncoated bead core.

Salts

This invention relates to sertraline acetate, which can be preparedaccording to the following procedure.

The free base of sertraline is dissolved in a suitable organic solventsuch as ethyl acetate; an unsaturated hydrocarbon such as hexane orpentane; an aromatic hydrocarbon, such as benzene or toluene; or acyclic or acyclic ether such as dioxane, tetrahydrofuran, diethyl etheror methoxymethyl ether or a combination thereof or a combination of anyof those solvents with water. A suitable organic solvent is any solventin which the free base of sertraline is freely soluble, in which theacetate salt of sertraline is particularly insoluble and whichfacilitates the formation of the desired crystalline form. Hexane ispreferred due to its ability to dissolve sertraline, its inability todissolve sertraline acetate and for the quality of the crystals obtainedupon granulation therewith. The temperature of the solution ismaintained at room temperature or is raised to the boiling point of thesolvent being used. It is preferred to raise the temperature to slightlybelow the boiling point of the solvent being used, generally between 30°C. and 60° C. When hexane is used, it is preferred to raise thetemperature to approximately 40° C. An excess of acetic acid is thenadded to the reaction mixture. It is generally preferable to add one totwo equivalents of acetic acid for every equivalent of sertraline.Typically, 1.1 equivalents of acetic acid is added. When the reaction iscomplete, sertraline acetate generally precipitates. Occasionally, toobtain a better yield of said sertraline acetate, the reaction mixtureis cooled, generally to about room temperature or about 0° C. Afterprecipitation of the salt, it is generally advantageous to continue tostir or granulate the precipitate. When granulating, it is ordinarilypreferable to do so at room temperature or slightly above roomtemperature and no greater than 35° C. The crystals which form areisolated by filtration. The crystals of the acetate salt of sertralineare washed with hexane and are dried at elevated temperature and reducedpressure, generally 30-60° C. for 24 to 48 hours or a period of timesufficient to remove substantially all traces of hexane and anyunreacted acetic acid.

Alternatively, sertraline acetate can be prepared directly from a saltof sertraline, for example, sertraline hydrochloride or sertralinemandelate, without isolation of the free base form of sertraline.Typically, sertraline hydrochloride is used in this preparation. Whenusing this procedure, said salt of sertraline is slurried in water anddilute aqueous base is added dropwise or in small portions. The pH ofthe solution is monitored during the addition of base to prevent theaddition of an excessive amount of base. Typically, the pH is maintainedbetween about 6.5 to 9.5. Preferably, the pH is maintained at 8.5.Suitable aqueous bases which can be used in this reaction include sodiumhydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate andpotassium bicarbonate. Preferably, aqueous sodium hydroxide is used. Thefree base of sertraline thus formed is partitioned into an immiscibleorganic solvent such as hexane, ethyl acetate, benzene, toluene orethers such as diethyl ether, dioxane or methoxymethyl ether. Generally,hexane is preferred. The immiscible organic phase is separated from theaqueous phase and the organic phase is washed with water to removechloride ions. The organic phase containing the free base form ofsertraline is then treated as disclosed in the previous paragraph toafford sertraline acetate.

This invention also relates to sertraline L-acetate, which can beprepared according to the following procedure.

The free base of sertraline is dissolved in a suitable organic solventsuch as ethyl acetate; an unsaturated hydrocarbon such as hexane orpentane; an aromatic hydrocarbon, such as benzene or toluene; or acyclic or acyclic ether such as dioxane, tetrahydrofuran, diethyl etheror methoxymethyl ether or a combination thereof or a combination of anyof those solvents with water. A suitable organic solvent is any solventin which the free base of sertraline is freely soluble, in which theL-lactate salt of sertraline is particularly insoluble and whichfacilitates the formation of the desired crystalline form. Ethyl acetateis preferred due to its ability to dissolve sertraline, its inability todissolve the sertraline L-lactate and for the quality of the crystalsobtained upon granulation therewith. The temperature of the solution ismaintained at room temperature or is raised to the boiling point of thesolvent being used. It is preferred to raise the temperature to slightlybelow the boiling point of the solvent being used, generally between 30°C. and 60° C. When ethyl acetate is used, it is preferred to raise thetemperature to approximately 40° C. An excess of L-lactic acid is thenadded to the reaction mixture. It is generally preferable to add one totwo equivalents of L-lactic acid for every equivalent of sertraline.Typically, 1.1 equivalents of L-lactic acid is added. When the reactionis compete, sertraline L-lactate generally precipitates. Occasionally,to obtain a better yield of sertraline L-lactate, the reaction mixtureis cooled, generally to about room temperature or about 0° C. Afterprecipitation of the salt, it is generally advantageous to continue tostir or granulate the precipitate. When granulating, it is ordinarilypreferable to do so at room temperature or slightly above roomtemperature and no greater than 35° C. The crystals which form arecollected by filtration. The crystals of the L-lactate salt ofsertraline are washed with ethyl acetate or hexane and are dried atelevated temperature and reduced pressure, generally 30-60° C. for 24 to48 hours or a period of time sufficient to remove substantially alltraces of solvent and any unreacted L-lactic acid.

Alternatively, sertraline L-lactate can be prepared directly from a saltof sertraline, for example, sertraline hydrochloride or sertralinemandelate, without isolation of the free base form of sertraline.Typically, sertraline hydrochloride is used in this preparation. Whenusing this procedure, sertraline hydrochloride is slurried in water anddilute aqueous base is added dropwise or in small portions. The pH ofthe solution is monitored during the addition of base to prevent theaddition of an excessive amount of base. Typically, the pH is maintainedbetween about 6.5 to 9.5. Preferably, the pH is maintained at 8.5.Suitable aqueous bases which can be used in this reaction include sodiumhydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate andpotassium bicarbonate. Preferably, aqueous sodium hydroxide is used. Thefree base of sertraline thus formed is partitioned into an immiscibleorganic solvent such as hexane, ethyl acetate, benzene, toluene orethers such as diethyl ether, dioxane or methoxymethyl ether. Generally,ethyl acetate is preferred. The immiscible organic phase is separatedfrom the aqueous phase and the organic phase is washed with water toremove chloride ions. The organic phase containing the free base form ofsertraline is then treated as disclosed in the previous paragraph toafford sertraline L-lactate.

Sertraline L-lactate may also be prepared directly from sertralinemandelate. When using this procedure, sertraline mandelate, which isprepared by the method described in U.S. Pat. No. 4,536,518, is slurriedin a mixture of water and a suitable organic solvent. Suitable organicsolvents for this reaction include ethyl acetate; unsaturatedhydrocarbons such as hexane or pentane; aromatic hydrocarbons, such asbenzene or toluene; and cyclic or acyclic ethers such as dioxane,tetrahydrofuran, diethyl ether and methoxymethyl ether. The slurry isgenerally cooled to a temperate below room temperature such as 0° C. to20° C. Typically the reaction mixture is cooled to about 15° C. The freebase of sertraline is then generated by the addition of a suitable base.Suitable bases for this reaction include sodium hydroxide, sodiumcarbonate, sodium bicarbonate, potassium carbonate and potassiumbicarbonate. Preferably aqueous sodium hydroxide is used. Enough base isadded to the reaction mixture to ensure complete conversion of thesertraline mandelate to sertraline free base. Typically this conversionis complete when the pH of the aqueous layer is at about 9.6. Theorganic layer, containing sertraline free base, is separated from theaqueous portion and the aqueous portion is generally extracted withadditional portions of organic solvent. The organic layers are combinedand concentrated. Filtration may occasionally be necessary to clarifythe solution. L-lactic acid is added directly to this solution and thereaction mixture is generally stirred for an extended period togranulate the sertraline L-lactate which forms. Typically the stirringis continued for 8 to 48 hours and preferably for about 16 to 24 hours.The sertraline L-lactate is then isolated and purified as disclosedhereinabove.

This invention also relates to crystalline sertraline L-aspartate, whichcan be prepared according to the flowing procedure.

The free base of sertraline is dissolved in a suitable organic solventsuch as ethyl acetate; an unsaturated hydrocarbon such as hexane orpentane; an aromatic hydrocarbon such as benzene or toluene; or a cyclicor acyclic ether such as dioxane, tetrahydrofuran, diethyl ether ormethoxymethyl ether or a combination thereof or a combination of any ofthose solvents with water. A suitable solvent is any solvent orcombination of solvents in which the free base of sertraline is freelysoluble, in which the L-aspartate salt of sertraline is particularlyinsoluble and which facilitates the formation of the desired crystallineform. Ethyl acetate in combination with a small amount of water ispreferred due to its ability to dissolve sertraline and L-aspartic acid,its inability to dissolve the sertraline L-aspartate and for the qualityof the crystals obtained upon granulation therewith. It is preferred touse a solution of ethyl acetate containing two to three percent water.It is especially preferred to use a solution of ethyl acetate containingthree percent water. The temperature of the solution is maintained atroom temperature or is raised to the boiling point of the solvent beingused. It is preferred to maintain the temperature at room temperature.An excess of aspartic acid is then added to the reaction mixture. It isgenerally preferable to add one to two equivalents of aspartic acid forevery equivalent of sertraline. Typically, 1.1 equivalents of asparticacid is added. When reaction is complete, sertraline L-aspartategenerally precipitates. Occasionally, to obtain a better yield ofsertraline L-aspartate, the reaction mixture is cooled, generally toabout room temperature or about 0° C. After precipitation of the salt,it is generally advantageous to continue to stir or granulate theprecipitate. When granulating, it is ordinarily preferable to do so atroom temperature or slightly above room temperature and no greater than35° C. The crystals which form are collected by filtration. The crystalsof the L-aspartate salt of sertraline are washed with ethyl acetatesaturated with water and are dried at elevated temperature and reducedpressure, generally 30-60° C. for 24 to 48 hours or a period of timesufficient to remove substantially all traces of ethyl acetate, waterand any unreacted aspartic acid.

Alternatively, sertraline L-aspartate can be prepared directly from asalt of sertraline, for example, sertraline hydrochloride or sertralinemandelate, without isolation of the free base form of sertraline.Typically, sertraline hydrochloride is used in this preparation. Whenusing this procedure, sertraline hydrochloride is slurried in water anddilute aqueous base is added dropwise or in small portions. The pH ofthe solution is monitored during the addition of base to prevent theaddition of an excessive amount of base. Typically, the pH is maintainedbetween 6.5 to 9.5. Preferably, the pH is maintained at 8.5. Suitableaqueous bases which can be used in this reaction include sodiumhydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate andpotassium bicarbonate. Preferably, dilute sodium hydroxide is used. Thefree base of sertraline thus formed is partitioned into an immiscibleorganic solvent such as hexane, ethyl acetate, benzene, toluene orethers such as diethyl ether, dioxane or methoxymethyl ether. Generally,two to three percent aqueous ethyl acetate is preferred. The immiscibleorganic phase is separated from the aqueous phase and the organic phaseis washed with water to remove chloride ions. The organic phasecontaining the free base form of sertraline is then treated as disclosedin the previous paragraph to afford sertraline L-aspartate.

The free base of sertraline is prepared as disclosed in U.S. Pat. No.4,536,518 or by neutralizing an aqueous solution of a salt of sertralinesuch as; for, example, sertraline hydroxide or sertraline mandelate withan aqueous base such as sodium hydroxide, sodium carbonate, sodiumbicarbonate, potassium carbonate or potassium bicarbonate. The free baseof sertraline can be used in solution or can be isolated as acrystalline solid.

Sertraline hydrochloride and sertraline mandelate are prepared by themethods disclosed in U.S. Pat. No. 4,536,518.

The hygroscopicities of sertraline acetate, sertraline L-lactate andsertraline aspartate are measured using a moisture microbalance such asthe VTI moisture balance (VTI Moisture Microbalances, MB 300 G and MB300 W, VTI Corporation, Hialeah, Fla., USA). sertraline acetate,sertraline L-lactate and sertraline acetate are exposed to atmosphereshaving a range of humidity from 10% to 90% humidity. A temperature of25° C. is maintained during all hygroscopicity measurements. Themoisture adsorption and desorption isotherms of sertraline acetate,sertraline L-lactate and sertraline aspartate in those atmospheres aredetermined using the VTI moisture microbalance. Sertraline acetate,sertraline L-lactate and sertraline aspartate are not hygroscopic overthe range of humidities studied.

The mechanical properties of sertraline acetate and sertraline L-lactateare determined by testing the compression stress, solid fraction,dynamic indentation, reduced elastic modulus, quasistatic indentation,elastic modulus, shear modulus and tensile strength thereof. Table 1displays the results of the testing of mechanical properties ofsertraline acetate.

TABLE 1 Mechanical Properties of Sertraline Acetate Property TestSertraline acetate Compression Stress, Mpa Compact Preparation 36.7(2.5) Solid Fraction Compact Preparation  0.831 Dynamic IndentationHard., Dynamic Indentation 60.0 (0.4) Mpa Reduced Elastic Modulus,Dynamic Indentation  5.1 (0.5) GPa Quasistatic Indentation QuasistaticIndentation 25.1 (1.3) Hard., Mpa Elastic Modulus, Gpa QuasistaticIndentation  2.2 (0.2 Shear Modulus, Mpa Quasistatic Indentation 99.9(19.1) Tensile Strength, Mpa Tensile Fracture  0.52 (0.03)

Table 1a displays the results of the testing of mechanical properties onsertraline L-lactate.

TABLE 1a Mechanical Properties of Sertraline L-lactate Property TestSertraline-L-lactate Compression Stress, Mpa Compact Preparation  52.8(0.7) Solid Fraction Compact Preparation  0.862 Dynamic IndentationHard., Dynamic Indentation  81.6 (1.6) Mpa Reduced Elastic Modulus,Dynamic Indentation  7.4 (0.6) GPa Quasistatic Indentation QuasistaticIndentation  31.1 (1.4) Hard., Mpa Elastic Modulus, Gpa QuasistaticIndentation  2.0 (0.2) Shear Modulus, Mpa Quasistatic Indentation 113.9(4.6) Tensile Strength, Mpa Tensile Fracture  0.56 (0.02)

Mechanical properties such as tensile strength, elastic modulus andhardness of pharmaceutical compacts (of drug, excipient as well as drugand excipient) cannot be estimated by standard methods used inmetallurgy because pharmaceutical solids cannot be compressed intohomogeneous fully dense bodies. In general the following four categoriesof mechanical properties are routinely evaluated: elastic, viscoelastic,plastic and fracture. All four categories contribute towards the threeevents of a compaction process, i.e., compression, dwell anddecompression. The estimation of mechanical properties of pharmaceuticalpowders is difficult because critical parameters which influence themeasurement of mechanical properties such as particle size distribution,crystal habit surface texture, degree of crystallinity andcrystallographic symmetry vary considerably in these materials. However,indices of tableting performance (hereinafter termed “ITP”) are used forpredicting the tableting performance of pharmaceutical compacts(Hiestand, E. N., Smith, D. P. Powder Tech., 38: 146-159, 1984;Hiestand, E. N., Smith, D. P. Adv. Ceram., 9: 47-57, 1984). Theseindices are derived from critical measurements made to assess themechanical response of the compacts (measurements are not made duringthe process of compaction). By measuring and calculating thesemechanical properties a person skilled in the art can understand thefundamental properties of the pharmaceutical powder. This understandingallows the skilled person to determine whether a tablet dosage form canbe manufactured. Measurement and calculation of the ITP mechanicalproperties such as tensile strength, indentation modulus and hardness ofthe compressed compact is accomplished according to procedures describedby Hiestand (J. Pharm. Sci., 60: 758-763, 1971; J. Pharm. Sci, 63:605-612, 1974; J. Pharm. Sci., 74: 768-770, 1985; PharmaceuticalTechnology, 8: 54-66, 1989; Int. J. Pharm., 67: 217-229, 1991; Int. J.Pharm., 67: 231-246, 1991).

The measurements of mechanical properties can be routinely accomplishedusing square compacts of the pure drug substance, in this casesertraline acetate and sertraline L-lactate. The measurements are madein triplicate and the compacts are prepared by uniaxial compression andtriaxial decompression.

The most critical material properties that influence powder compactionare its ductility, elasticity and tensile strength. Ductility isdetermined by pendulum impact and is a dynamic indentation test todetermine the hardness of the compact. The hardness of the compound isinversely related to its ductility. Since plastic deformation enhancesinterparticle bonding, high ductility or low hardness is most desirable.Typically, dynamic indentation hardness values below 100 Mpa are high;values in the 100-200 MPa range are marginal and values greater than 200MPa are low.

The elastic modulus (also known as Young's modulus) of the compact isdetermined by measuring the amount of dent recovery after a prolonged(quasielastic) indentation hardness test. It is desirable to have lowelastic response of the material during decompression which implies thatthe material should exhibit low elastic modulus. Elasticity values ofgreater than 8 GPa are high, values between 1-8 GPa are moderate andvalues less than 1 GPa are low.

Tensile strength is measured by transverse compression of the compactsuntil it results in tensile fracture. It is desirable to have hightensile strength. Tensile strength of greater than 2 MPa is high, valuesin the range of 0.8-2.0 Mpa are moderate and values less than 0.8 MPaare low.

Hiestand's ITP is comprised of the following characteristics: brittlefracture index (herein termed BFI), best case bonding index (hereintermed bBI), worst case bonding index (herein termed wBI) and strainindex (herein termed SI).

The BFI is a measure of the propensity of a compact to break or fragmentunder stress from existing cracks and holes in the compact. BFI is usedby the skilled person to indicate the propensity of a tablet to break orfragment during processing (i.e. failure) such as during ejection from atablet press or during film coating. A brittle fracture index value of 0is excellent, values in the range of 0.01-0.09 are good; values in therange of 0.1-0.19 are marginal and values of 0.2-1.0 are poor.

Bonding index is an estimate of the capacity of a compact to retaininterparticulate bonds during elastic recovery. Hiestand has attributedthe process of plastic deformation as the principal mechanism forformation of tablet bonds when a pharmaceutical powder is subjected tostress under a load. The estimate of plastic deformation is used incalculating the bonding index. The estimation of bonding index isimportant since decompression is a major step in the manufacture oftablets. The worst case bonding index (wBI) and best case bonding index(bBI) assess the ability of the interparticulate bonds that have beenformed during compression to survive the release of strain energy duringcompression. Under conditions of high speed manufacture of tablets wBIis more applicable than bBI. Bonding index values of greater than orequal 2 are excellent; values between 0.8-1.9 are good; values between0.3-0.7 are marginal and values less than 0.3 are poor.

The strain index is a measure of the elastic recovery of the compact. Itcan also be stated to be a measure of be extent of elastic recoveryduring the unloading phase. Elastic recovery from an indentation processcan be utilized as an estimate of the elastic modulus.

Samples for the test of mechanical properties are prepared according tostandard procedures. To generate reliable data, such samples must befree of mechanical flaws, such as microcracks. Therefore, a specializedtablet press, prepared as described in U.S. Pat. No. 4,880,373, isutilized. This press compresses the powder uniaxially (i.e., in onedimension) and then slowly decompresses the powder triaxially (i.e., inthree dimensions). The samples are compressed to a given degree ofcompaction, termed the reference state. This allows the mechanicalproperty data to be compared to other materials which have beencompressed to the same reference state. The standard compactionprocedure is to compact powders to a solid fraction of 0.85. Solidfraction, or relative density, is the apparent density of the compactdivided by the true (absolute) density of the compact. The apparentdensity of the compact is determined by measuring the volume thereof anddividing by the mass. This measurement is usually made in cubiccentimeters per gram. The true density of the powder is determined byhelium pycnometry. Ordinarily, to achieve the desired solid fraction,trial compactions of carefully weighed powder samples must be performedand the solid fraction of the resultant compact is measured. Adjustmentsto solid fraction are achieved by increasing or decreasing the powderweight.

The square compacts which serve as the test specimens are prepared usingthe triaxial decompression tablet press, prepared as described in U.S.Pat. No. 4,880,373, with a square split die and 1.9 cm square upper andlower punches. The prelubricated die and lower punch are mounted in thetablet press and the die is filled with the preweighed powder. Thepowder surface is smoothed with a spatula and the upper punch is placedin the die on top of the powder. To ensure a high level of precision,the process is ordinarily computerized. The die hydraulic ram is broughtto full extension, pressing the die halves tightly together. Next, thepunch ram is brought to full extension, compressing the powderuniaxially. Once the ram reaches full extension, it remains so for afive minute dwell period. During this dwell, the punch and die forcesrelax due to stress relaxation in the sample. At the end of the dwell,the computer bleeds off the metal-to-metal forces on the punch and diehydraulic cylinders and then begins the triaxial decompression for 15minutes. During this phase the punch and die forces are simultaneouslyslowly backed off, keeping the pressures at a 1-to-1 ratio, untilreaching the minimum forces attainable by the hydraulic system. Thefinished compact is then retrieved and the process repeated. Center holecompacts are prepared in the same manner except that the lower punch hasa spring-loaded pin installed in it. Usually the center hole passesthrough about 75% of the compact. A micro drill press, fitted with a bitthe same diameter as the punch pin, is used complete the hole. Allsamples are allowed to relax for an 18 to 24 hour period prior totesting.

The relaxed compacts are used as the test specimens for the mechanicalmeasurements. The following table summarizes the testing techniques, thekey measurements, and the properties determined by the tests.

TABLE 2 Mechanical Property Testing Techniques and Measurements DerivedTechnique Key Measurements Measured Properties Properties Indenta-Initial Height, h_(i) Dynamic Hardness, 1 Reduced Elastic tion Hard- 2Rebound Height, H₀ Modulus, E′ ness h_(r) 2 Viscoelastic 3 ChordalRadius, a Constant, VE 3 Worst Case Bonding Index, Bl_(W) 4Brittle/Visco- elastic Bonding Index, bBl_(V) Indenta- 1 Relaxed Force,F 1 Quasi-Static 1 Best Case tion Hard- 2 Chordal Radius, a Hardness,H₁₀ Bonding ness 2 Shear Modulus, G Index, Bl_(b) 2 ViscoelasticConstant, VE 3 Elastic Modu- lus, E Fracture 1 Force, F 1 TensileStrength, 1 Worst Case 2 Compact σ_(T) Bonding Index, Thickness, TBl_(W) 2 Best Case Bonding Index, Bl_(b) 3 Brittie Fracture Index, BFI 4Brittle/Visco- elastic Bonding Index, bBl_(V) Fracture 1 Force, F 1Compromised 1 Brittle Fracture 2 Compact Tensile Strength, Index, BFIThickness, T σ_(T0) Powder 1. Shear Strength, 1 Effective Angle of 1Uniform Flow Flow Internal Friction, Number, UFN

Dynamic indentation hardness, H₀, of the compacts is measured with apendulum impact apparatus, prepared as described in U.S. Pat. No.4,885,933. The compact is mounted in pneumatically-powered clamps with asolid backing behind the compact. The spherical pendulum has a knownmass and diameter and is poised at a predetermined initial angle beforerelease. The pendulum is released toward the compact, strikes thecompact and rebounds. The time required for the pendulum to pass betweentwo photocells of given distance apart is measured and the pendulumrebound height, h_(r) is automatically calculated. These measurementsand calculations are conveniently made by a computer. The dented compactis removed from its clamps and it is mounted on a surface profilometer(Surfanalyzer 5000, Federal Products, Inc., Providence, R.I.). Thisinstrument's probe is carefully positioned and then it scans the dentsurface by traversing across it. Three parallel scans are performed oneach dent. The first is performed across the dent center, and the secondand third equidistant are performed on either side of the first scan.The profile data of all three scans are saved and analyzed by performingcircular curve fitting to determine the dent's chordal radius and tocalculate H₀ according to equation (1),

H ₀=((4mgrh _(r))/πa ⁴)*((h _(i)/h _(r))−0.375)  (1),

where m and r are the indentor's mass and radius, g is the gravitationalconstant, a is the dent's chordal radius and h_(i) and h_(r) are theinitial and rebound heights of the indentor.

Quasistatic indentation hardness, H₁₀, is determined by slowly pushing amotor-driven spherical indentor, prepared as described in U.S. Pat. No.4,957,003, into the surface of a compact to a predetermined distance andholding it in that position for a fixed period of time. This is termedthe dwell period. The indentor is generally held in position for aboutfive to twenty minutes and preferably for ten minutes. At the end of thedwell period, the force on the indentor is recorded. The compact isremoved, its dent scanned and analyzed as described above for thependulum test and H₁₀ is calculated according to equation (2),

 H ₁₀ =F _(r)/(πa ²)  (2),

where F_(r) is the relaxed force on the indentor after the dwell timeand a is the dent's chordal radius. The compact is held in place bypneumatically powered clamps. The indentor diameter is the same as thependulum's diameter (2.54 cm). The penetration depth of the quasistaticindentor is such that the chordal radius of the dent would match thatproduced in the impact test.

The tensile strength of regular compacts, σ_(T), is determined by thetransverse compression of the compact to fracture between a stationaryplaten and a motor-driven platen of given width. The force on theplatens is monitored continuously and a force-time profile is displayedon the computer screen after the test. The profile is analyzed byidentifying the point of fracture which usually exhibits a sharp drop inforce. An event marker is also used to help identify the break when thesample visibly cracks. The tensile strength is then calculated accordingto equation (3),

σ_(T)=F _(break)/(W _(p) *T)*PTF  (3)

where W_(p) is the platen width, T is the thickness of the compact andPTF is the perpendicular tensile force which is 0.16 when the platenwidth is 40% of the compact width. The rate of compression in the testis monitored by calculating a time constant and adjusting the platenspeed such that the time constant lies between ten and twenty seconds.With equivalent time constants; material viscoelastic effects areavoided. The time constant is defined as the time in seconds on theforce-time profile between F_(break) and F_(break)/e, where F_(break) isthe force at which the compact fractures and F_(break)/e is an exponent.The time difference between F_(break) and F_(break)/e is defined as the“time constant”. This normalization of time constant is incorporatedinto the calculations to eliminate the contributions fromviscoelasticity of the material towards its fracture.

The compromised tensile strength, σ_(T0), is measured on center-holecompacts using the same apparatus and motor speed settings as in theregular tensile strength test. It is calculated according to equation(3) above.

Powder flow evaluations are performed using a simplified plate-typeshear cell on the non-compacted powders after they have equilibrated atleast 18 hours to a given relative humidity (RH), usually 50%, atambient temperature. Shear cells are prepared as described in Hiestandand Wilcox, J. Pharm. Sci., 1969, 58, 1403-10; Hiestand et al., J.Pharm. Sci., 1973, 62, 1513-1517; and Hiestand and Wells, ProceedingsInternational Powder and Bulk Solids Handling and Processing Conference,Rosemnont, Ill., May 10-12 (1977). A circular bed of powder, 4 to 6 mmthick and 63.5 to 82.5 mm in diameter, is formed on a coarse sandpapersurface using a template. The template is removed and a sled, which isattached to a load cell by a tow line, is placed on the powder. A weightis placed on the sled and the machine's motor is started which pulls theweighted sled across the powder. The pulling force is continuouslymeasured by the load cell. The force rapidly increases to a maximumuntil the sled begins to move across the powder in a shearing action atwhich point a force reduction is observed. The motor's direction is thenreversed until the tow line goes slack. The motor then pulls again to amaximum force and the motor direction again reversed. The process isrepeated several times more until the force maxima is reproducible. Thepowder bed is then manipulated to its previous shape. The sled, carryingidentical weight, is placed back on top of the powder. The above processis repeated until the plateau force is obtained. The powder bed isreformed and the entire process repeated with a different weight on thesled. The effective angle of internal friction is calculated as the arctangent of the slope of the plot of plateau shear stress versusconsolidation stress. This parameter is used to calculate the UniformFlow Number, UFN, as shown in equation (4),

UFN=0.667*(42-δ)  (4),

where δ is the effective angle of internal friction.

Sertraline acetate does not possess any deficiencies that impede theformation and preservation of particle bonds during compression anddecompression. Specifically, sertraline acetate was found to have highductility and relatively low elastic modulus. Overall, sertralineacetate has exceptional mechanical properties and particle bondingability and thus is an excellent candidate for tablet manufacture.

The values for the intrinsic mechanical properties of the lactate saltindicate that it possesses no weaknesses which would impede particlebond formation and preservation during compression and decompression.The tensile strength of sertraline L-lactate was found to be very high.Further, the compression stress of the lactate salt of sertraline wasgreater than its hardness. Values for the tabletting indices of thelactate salt of sertraline suggest it is an excellent candidate fortablet manufacture. Overall, sertraline L-lactate has exceptionalmechanical properties, particle bonding ability and tabletting indexvalues. Thus, sertraline L-lactate is an excellent candidate for tabletmanufacture.

Crystallinity of sertraline acetate, sertraline L-lactate and sertralineL-aspartate are determined by polarized light microscopy and powderX-ray diffraction. The powder X-ray diffraction pattern is determined atambient temperature using an X-ray diffractometer (Diffraktometer 5000,Siemens Analytical X-ray Systems, Inc., 6300 Enterprise Lane, Madison,Wis. 53719-1173). Typically samples are placed in an aluminum holder andare scanned with the diffraction angle, 2θ, increasing from 5° to 35°,with a step size of 0.02° and a counting time of one second. The thermalcharacteristics, melting point, heat of fusion and loss in weight duringheating were determined using two instruments: Differential ScanningCalorimeter (DSC 4, Perkin Elmer, USA) and Thermogravimetric Analyzer(SSC 5200, Seiko, Japan).

To determine the solubility of sertraline acetate, sertraline L-lactateand sertraline L-aspartate, an aliquot of sertraline acetate, sertralineL-lactate or sertraline L-aspartate is added to a measured amount ofwater in a screw cap vial. To accelerate the attainment of equilibriumthe saturated solution can be prepared at a temperature higher thanambient temperature. The vial is placed on a rotator that is immersed ina water bath at 40° C. At this temperature enough sertraline salt isadded until excess solid is present in the vial. The vial is maintainedat 40° C. for 6 hours at which time the temperature is lowered to 15° C.for two hours. The temperature of the vial is then adjusted to 25° C.and is maintained at this temperature for up to two days. At the end ofthe equilibration time, the solution is filtered, the pH of the filtrateis measured and an aliquot of the filtrate is assayed by reverse phaseHPLC to determine the concentration of sertraline in solution. The HPLCassay is performed using a Waters Symmetry C-18, 250×4.6 mm column,eluted at 1.0 mL/min. with a mobile phase solution. The column can bepurchased from Waters Corp., 34 Maple Street, Milford, Mass. 01757. Themobile phase solution is prepared by mixing 270 mL of tetrahydrofuran,230 mL of methanol and 400 mL of buffer. The buffer is prepared byadding 1.7 mL of phosphoric acid and 3.5 mL of triethylamine to oneliter of water. The excess solid in the vial is collected, dried andthen investigated for its crystallinity using microscopy and thermalanalysis. The instant acetate salt of this invention has a watersolubility of 84 mg/ml. The instant L-lactate salt of sertraline of thisinvention has a water solubility of 125 mg/mL. The instant L-aspartatesalt of sertraline of this invention has a water solubility of 28.6mgA/mL. This high degree of water solubility permits more sertraline tobe delivered over a shorter period of time, which is particularly usefulfor acute indications. Furthermore, a high solubility is advantageous inosmotic oral controlled release dosage forms which deliver a solution ofsertraline in a controlled fashion.

The chemical stabilities of sertraline acetate, sertraline L-lactate andsertraline L-aspartate are determined using reverse phase highperformance liquid chromatography (reverse phase HPLC, same conditionsas above) assay of samples that have been subjected to acceleratedstability challenge. In an accelerated stability challenge, samples ofsertraline acetate are subjected to varying combinations of humidity andtemperature conditions for varying lengths of time. The followingcombinations of humidity and temperature are particularly useful inevaluating the chemical stability of sertraline and various salt formsthereof. The activity of sertraline acetate as well as the presence ofimpurities and decomposition products is quantitated in theseinvestigations. Generally a drug is considered stable if the amount ofnew impurities detected is less than 0.1% of the amount of the drugused. The stability of sertraline acetate, sertraline L-lactate andsertraline L-aspartate in the solid state as well as in solution wasdetermined.

Accelerated stability testing is conducted by subjecting sertralineacetate, sertraline L-lactate or sertraline L-aspartate to standard testconditions of temperature and humidity as defined by the ICH(International Conference on Harmonization of Technical Requirements forthe Registration of Pharmaceuticals for Human Use) Guidelines.Generally, a sample of sertraline acetate, sertraline L-lactate orsertraline L-aspartate is evaluated at 40° C.±2° C./75% RH±5% for aperiod of 24 weeks. In addition samples are placed under the followingconditions: 50° C.±2° C./20% RH for 24 weeks; 70° C.±2° C./RH≦10% for 3weeks. Stability of sertraline acetate, sertraline L-lactate orsertraline L-aspartate is also evaluated by placing it in 0.01 Nhydrochloric acid solution for 6 weeks at 50° C. and in 0.01 N sodiumhydroxide solution for 6 weeks at 50° C. All of the samples subjected tostability testing are evaluated for purity and decomposition byperforming a reverse phase HPLC analysis, using the same conditions asdescribed above. When the above experiments are performed on sertralineacetate, sertraline L-lactate or sertraline L-aspartate, no newdecomposition products were observed at levels greater than 0.1% of theparent compound. The purity of each of the sertraline acetate,sertraline L-lactate and sertraline L-aspartate samples was greater than99%.

In the treatment of the diseases and conditions disclosed herein andclaimed in the appendant claims, sertraline acetate, sertralineL-lactate or sertraline L-aspartate may be formulated as immediaterelease dosage forms as disclosed, for example, in U.S. Pat. No.4,536,518. Alternatively, sertraline acetate, sertraline L-lactate orsertraline L-aspartate may be formulated in a controlled release dosageform, such as a sustained release dosage form, an encapsulate solutiondosage form or a delayed release dosage form. The manner of making andusing such sustained release, encapsulated solution and delayed releasedosage formulations is disclosed in commonly-assigned copending U.S.applications entitled “Encapsulated Solution Dosage Forms ofSertraline”, and “Delayed Release Dosage Forms of Sertraline”,respectively, and having Pfizer docket numbers PC9838JTJ and PC9824JTJ,respectively, each of which are PCT applications designating the UnitedStates and each of which is incorporated herein by reference.

In general, sertraline acetate, sertraline L-lactate and sertralineL-aspartate are normally administered in dosages ranging from about 0.2mgA/kg of body weight per day to about 10 mgA/kg of body weight per day,although variations will necessarily occur depending upon the conditionsof the subject being treated and the particular route of administrationchosen. Typically, a preferred range of dosages is about 15 mgA ofsertraline acetate, sertraline L-lactate or sertraline L-aspartate perday to about 200 mgA of sertraline acetate, sertraline L-lactate orsertraline L-aspartate per day for average adult subjects having a bodyweight of about 70 kg. However, the preferred dosage amount will dependupon the dosage form in which sertraline acetate, sertraline L-lactateor sertraline L-aspartate is administered as well as other factors whichwill be readily apparent to a person skilled in the art, such as aphysician.

Where used herein, the abbreviation “Mpa” means megaPascals and theabbreviation “Gpa” means gigaPascals.

Where used herein, the term “osmotic tablets” defines a controlledrelease solid dosage form powered by osmotic pressure.

For convenience and consistency, reference to “sertraline” in terms oftherapeutic amounts or in release rates in the claims is to activesertraline, abbreviated herein as “mgA”, i.e., the non-salt,non-hydrated free base having a molecular weight of 306.2 g/mole.Amounts in mgA can conveniently be converted to equivalent weights forsertraline acetate, which has a molecular weight of 368.3 g/mole. Themolecular weight of the ¼-hydrate form of sertraline acetate is 370.8g/mole. The molecular weight of sertraline L-lactate is 396.3 g/mole.The molecular weight of sertraline L-aspartate is 439.3 g/mole.

The invention will now be illustrated by the following examples whichare not to be taken as limiting. In general, the examples demonstratethe incidence of gastrointestinal side-effects upon oral and IV dosingof sertraline, the amelioration of these side effects by controlledrelease dosing, and the preparation of sustained-release dosage forms ofsertraline within the scope of this invention, salts, processes formaking same, and so forth.

In the examples that follow, the following definitions and tests havebeen employed:

1. “Q” is used to designate a quantity of sertraline either in mgA or inpercent (%), as indicated. The Q is associated with a time or “pullpoint” at which an indicated aliquot of solution was removed for assayof sertraline, the time of removal or pull point being designated inhours as a subscript. Thus, a “Q₁” of 15% means that 15% of thesertraline dose was dissolved in 1 hour.

2. Specification of a quantity in percent (%) means percent by weightbased on total weight, unless otherwise indicated.

3. “t_(80%)” means the time, in hours, for 80% of sertraline dose to bereleased from the dosage form.

4. Release rate is defined by the following equation:

release rate=0.8*(dose)/t_(80%) or Q₂₄/24 if 80% of the sertraline isnot released within 24 hours

5. “Surelease®” is the registered trademark of Colorcon Inc., WestPoint, Pa. for an aqueous, fully plasticized polymeric dispersion ofethylcellulose.

6. “Opadry®” is the registered trademark of Colorcon Inc., West Point,Pa. for a family of plasticized cellulose ethers which includehydroxypropyl methylcellulose, hydroxypropyl cellulose andmethylcellulose that are supplied as powders for reconstitution inwater.

7. “mgA” is an abbreviation for “milligrams of active sertraline”. Forexample, “200 mgA” means 200 mg of active sertraline.

8. “X mgA of multiparticulate” (where X is a number) means the amount ofmultiparticulates containing X mgA. For example, “100 mgA ofmultiparticulates” means the weight of multiparticulates containing 100mg active sertraline.

9. In Vitro Dissolution Test: The following in vitro test can be used toscreen sustained release embodiments of this invention for in vivosuitability. If a particular dosage form satisfies the in vitro criteriaor the in vivo criteria disclosed herein, it is within the scope of thisinvention.

Sustained release dosage forms of sertraline are tested in a standardUSP rotating paddle apparatus as disclosed in United StatesPharmacopoeia XXIII (USP) Dissolution Test Chapter 711, Apparatus 2.Paddles are rotated at 50 rpm (or 100 rpm if the dosage form ismultiparticulate or disintegrates quickly into multiparticulates) andthe dissolution is conducted in, as the test medium, 900 mL acetatebuffer (0.13M acetic acid) with 0.075M sodium chloride using potassiumhydroxide to adjust pH to 4.0, at 37° C. The dissolution vessels arecovered to prevent evaporation. If gelatin capsules are used, then 0.1mg/mL of the enzyme trypsin must be added to the buffer. At indicatedtimes following test initiation (i.e. insertion of the dosage form intothe apparatus), filtered aliquots (typically 2 or 10 mL) from the testmedium are withdrawn and analyzed for sertraline by reverse-phase highperformance liquid chromatography (HPLC) or other suitable quantifiableanalysis method. Dissolution results are reported as mgA sertralinedissolved versus time or percent of active sertraline dissolved versustime. Sustained release dosage forms that meet the following criteriaare within the scope of the invention: during the initial time overwhich 80% of drug loading is released (1) the sertraline release rate isbetween 1 mgA/hr and 40 mgA/hr, as defined above; and (2) the sertralinerelease rate cannot exceed 40 mgA/hr during any one hour period; and,(3) less than 70% of the incorporated sertraline is released during thefirst hour in the use environment.

For a delayed plus sustained release embodiment wherein the delay istemporal, the same test as described immediately above for puresustained release embodiments is employed without any modification. Thedosage form will release sertraline at a rate less than 1 mgA/hr for aperiod of up to three hours or less, corresponding to the delay period,followed by sustained sertraline release at a rate of from 1 mgA/hr to40 mgA/hr thereafter.

A convenient test for a spatially delayed plus sustained releaseembodiment of the current invention is a modified version of a two partin vitro dissolution test, which is described in the 1995 US.Pharmacopoeia (USP 23), Section [724], Subsection “Delayed Release(Enteric-coated) Articles—General Drug Release Standard”, whichincorporates a 2 hr test of sertraline release in a simulated gastricfluid (“acid test”), followed by a test of drug release in a simulatedintestinal fluid (“neutral test”). For tablets and capsules which do notcontain multiparticulates or disintegrate rapidly intomultiparticulates, stirring is effected using paddles at 50 rpm. Formultiparticulates or dosage forms that disintegrate intomultiparticulates, stirring is effecting using paddles at 100 rpm. Ifgelatin capsules are used, then 0.1 mg/mL of the enzyme trypsin must beadded to the buffer. This two stage in vitro test is adjusted to beuseful in evaluating spatially delayed plus sustained embodiments ofthis invention, as now described.

For pH-triggered spatially-delayed plus sustained release embodiments,the in vitro test is carried out as described in the USP “Enteric Test”,with the requirements that dosage forms of the invention (a) releasesertraline at a rate not exceeding 1 mgA/hr for at least one hour duringthe “acid” phase of the test (in 0.1 N HCl), and (b) release sertralineat a rate between 1 mgA/hr and 40 mgA/hr in the neutral phase of thetest, provided that the dosage forms release no more than an additional70% of the incorporated sertraline in the first hour of the neutralphase of the test. If desired, the acid phase portion of the test can becarried out for longer than 1 hour, i.e., under even more stringentconditions and such embodiments are also within the scope of theinvention. Calculation of the sertraline release rate during the neutralphase of the test is as follows. The rate is calculated by noting thetime following the 1 hour delay during which an additional 80% of thedose has been released into the neutral (pH 6.8) medium, then carryingout a division in which the numerator is 80% of the dose in mgA, and thedenominator is the time at which an additional 80% of the dose isreleased into the neutral medium minus 1 hour (or other time period ifthe acid phase is longer than 1 hour). The acid portion of the test iscarried out in 750 ml 0.1N HCl, for 1 hr. After 1 hr, 250 ml 0.2Mtribasic sodium phosphate, containing 10 gm polysorbate-80, is added tothe acid medium (containing the dosage form), and the pH is adjusted topH 6.8, using either 2M hydrochloric acid or 2M sodium hydroxide. Thesolubility of sertraline is low in phosphate buffer (pH 6.8). Thuspolysorbate-80 (1% w/v) is added to the neutral (pH 6.8) phosphatemedium to increase the sertraline solubility to provide “sinkconditions” for dissolution.

For enzyme-triggered spatially-delayed plus sustained releaseembodiments described in this disclosure, release of sertraline is“triggered” by the presence of pancreatic lipase, esterase, or proteasein the small intestine. For in vitro evaluation of lipase-triggereddelayed plus sustained release dosage forms, 5 mg/ml porcine pancreaticlipase (Sigma Chem., St. Louis, Mo.) is included in the dissolutionmedium for the second neutral stage of the dissolution test. Foresterase- or protease-triggered delayed release systems, appropriateesterases or proteases (e.g. pancreatic esterase, trypsin, chymotrypsin,elastase) are included in the second stage of the in vitro test. Thusthe test is conducted in the same manner as for pH-triggered spatiallydelayed forms, but the neutral phase is conducted in the presence of anenzyme suitable for triggering the onset of sustained release. If theesterase, protease, or lipase is denatured by polysorbate-80, then thefirst hour of the “neutral” phase is carried out in the presence ofenzyme and absence of polysorbate-80. After one hour in the “neutral”phase, 10 g of polysorbate-80 is added.

EXAMPLE 1

This example demonstrates that sustained release dosing of sertraline(200 mg dose as sixteen 12.5 mg doses given at time zero and every hourfor 15 hr) results in decreased side effect severity, relative to asingle 200 mg bolus dose.

In a double-blind, randomized, placebo-controlled parallel group study,healthy male human subjects were divided into three groups. Group A,referred to as the “bolus dosing group”, received a single 200 mgsertraline dose as two 100 mg sertraline immediate release tablets(ZOLOFT®). The tablets were administered with 50 ml water. The bolusdosing group also received a 50 ml placebo solution every hour for 15hours. The placebo solution contained lactose, menthol, andpolyvinylpyrrolidone to mimic the appearance and mouth feet of thesertraline solution, to assure blinding. Group B, referred to as the“divided dosing group”, received the same total dose, administered as asolution of 125 mg sertraline solution in 50 ml of water at the rate ofone 125 mg dose each hour for 15 hours. Group B also received twoplacebo tablets at the fist dosing time. Group C, referred to as the“placebo group”, received placebo tablets and placebo solutions at theappropriate corresponding time points. All subjects were dosed after anovernight fast.

Blood samples were withdrawn prior to dosing, and at 0.5, 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24, 36, 48, 72, 96,120, 144, 168, 192, and 240 hr post-dosing. Plasma sertralineconcentrations were determined using capillary gas chromatography. Totalsystemic exposure to sertraline was determined by measuring the areaunder the plasma sertraline concentration vs. time curve (AUC) for eachsubject in a given group, and then by calculating a mean AUC for thegroup. C_(max) is the maximum observed plasma sertraline concentrationachieved in a subject. T_(max) is the time at which C_(max) is achieved.Plasma pharmacokinetic data for this example are presented in Table 1-1.

Prior to dosing and to each blood sampling time, each subject filled outa questionnaire, which consisted of a series of “Visual Analogue Scales”in which the subject was required to rate, on a scale of 0-10, theseverity of certain potential side effects. The subjects were instructedthat “0” indicated an absent effect and “10” indicated the worstpossible effect.

A total of 45 subjects completed this study: 15 each in Groups A, B, andC. For eight side effects evaluated at 30 time points, a total of 10,800individual visual-analogue-scale evaluations were obtained.

Table 1-1 demonstrates that the total systemic sertraline exposure ofthe two dosing groups, Groups A and B, as reflected in the AUC, wassimilar. For the divided dosing group, C_(max) was lower and T_(max) waslonger, as expected, because the dosing took place over 15 hr, ratherthan a single bolus dose. Three subjects in the 200 mg bolus dose grouphad emesis at 4.25, 11.2, and 7.6 hr. Since the emesis occurred aftersubstantial plasma concentrations were achieved in all three subjectsand after T_(max) in two, the data from these subjects were not treateddifferently than the data from other subjects. Subjects on the 15 hrdivided dose regimen experienced no emetic episodes. Thus the 15 hrdivided dose regimen exhibited a decreased incidence of emesis, relativeto the bolus dose regimen.

Analysis of side effect visual-analogue-scale data was carried out asfollows. For a particular side effect (e.g., abdominal pain) in aparticular subject, visual-analogue-scale scores over the 24 hrpost-dose period were summed to give a “cumulative score”. “Cumulativescores” for all members of a treatment group were summed, and divided bythe number of subjects in the group, to give a Mean Cumulative Score.The scale of this Mean Cumulative Score does not correspond to theoriginal 0-10 scale, since it reflects the summation of all non-zeroscores over the entire evaluation period. Table 1-2 presence MeanCumulative Scores for a series of gastrointestinal side effects:abdominal pain, nausea, urgency to defecate, regurgitation, diarrhea,and abdominal cramping. The non-gastrointestinal side effects dizzinessand tremor were also evaluated.

Table 1-2 demonstrates that the overall severity of sertraline-inducedside effects was lower for the 15 hr divided dose treatment.

TABLE 1-1 Sertraline Pharmacokinetics For a 200 mg Dose given as aSingle Dose, or as Sixteen 12.5 mg doses every Hour for 15 Hours (meanvalues). C_(max) T_(max) AUC_(O-last) TREATMENT (ng/ml) (hr) (ng.hr/ml)200 mg 74  6 1646 single dose (Group A) 12.5 mg per hr 32 16 1227 for 15hr (Group B)

TABLE 1-2 Mean Cumulative Visual Analog Score Data for Various SideEffects, averaged over all 15 subjects in each group. See text forexplanation of “mean cumulative score.” MEAN CUMULATIVE SCORE GROUP AGROUP B GROUP C SIDE EFFECT (Bolus Dose) (16 Divided Doses) (Placebo)Abdominal Pain 2.7 0.1 1.7 Nausea 17.5 2.6 1.2 Urgency to Defecate 3.10.5 0.6 Regurgitation 4.0 0.3 0.3 Abdominal 3.1 0.1 0.9 CrampingDiarrhea 3.9 0.2 0.2 Dizziness 13.8 0.5 6.8 Tremor 7.9 1.7 0.5

Example 1 further demonstrates that (1) side effects may be amelioratedby controlling the rate at which sertraline is released into thegastrointestinal tract, (2) delivery at a rate of 200 mg/15 hr=13.3mg/hr results in a decrease in gastrointestinal and systematic sideeffects compared to bolus dosing with the divided-dose side effectseverity at or near placebo levels (Table 1-2), and (3) sustainedrelease dosage forms which contain less than 200 mg sertraline also havean advantageous side effect profile. In the course of carrying out thefirst half of the 200 mg/15 hr divided dose study of this example, eight12.5 mg doses were delivered over 7 hr, with low observed side effectintensity (total dose 100 mg). Likewise, during the first quarter of the200 mg/15 hr divided dose study of this Example, four 12.5 mg doses weredelivered over 3 hr, with low observed side effect intensity (total dose50 mg).

From another perspective, side effects (particularly tremor anddizziness, which are systemically mediated, and not mediated by directcontact of sertraline with the gastrointestinal tract) may beameliorated by controlling the maximum sertraline concentration in thesystemic circulation after oral dosing. In this Example, the 16×12.5 mgdivided dose gave a C_(max) of 32 ng/ml, with very low side effectseverity. On the other hand, the 200 mg bolus dose gave a C_(max) of 74ng/ml, and exhibited significant side effects.

EXAMPLE 2

This example demonstrates that sustained release dosing of sertraline(200 mg dose as eight 25 mg doses given at time zero and every hour for7 hr) results in decreased side effect severity, relative to a single200 mg bolus dose.

In a double-blind, randomized, placebo controlled parallel group study,healthy male human subjects were divided into three groups. Group A(n=14) received a single 200 mg sertraline dose as two 100 mg sertralineimmediate release tablets (ZOLOFT®) (“bolus dosing” group). The tabletswere administered with 50 ml water. Group A also received a 50 mlplacebo solution every hr for 7 hr. The placebo solution containedlactose and menthol. Group B (n=16) received the same total dose,administered as a 25 mg sertraline solution (in 50 ml) at the rate ofone 25 mg dose each hr for 7 hr (“divided dosing” group). Group B alsoreceived two placebo tablets at the fist dosing time. Group C (n=15)received placebo tablets and placebo solutions at the appropriate timepoints. All subjects were dosed after an overnight fast.

Blood samples were withdrawn prior to dosing, and at 0.5, 1, 2, 3, 4, 5,6, 7, 8, 9, 11, 13, 15, 17, 24, 48, 72, 96, 120, and 144 hr post dosing.Plasma sertraline concentrations, C_(max), T_(max), and AUC were alsodetermined in the same manner. Plasma pharmacokinetic data for thisexample are presented in Table 2-1.

Prior to dosing and each blood sampling time, each subject filled out aquestionnaire, which consisted of a series of “Visual Analogue Scales”as described in Example 1. A total of 45 subjects completed this study.For three side effects evaluated at 30 time points, a total of 4,500individual visual-analogue-scale evaluations were obtained.

Table 2-1 demonstrates that the total systemic sertraline exposure ofthe two dosing groups, reflected in the AUC, was similar. For thedivided dosing group, C_(max) was lower and T_(max) was longer, asexpected because the dosing took place over 7 hr rather than in a singlebolus dose. Four subjects in the 200 mg bolus dose group had emesis at2.6, 2.8, 2.8, and 3.8 hr. The pharmacokinetic data from these foursubjects were not included in the averages presented in Table 2-1. Onesubject on the 7 hr divided dose regimen had emesis at 12.6 hr. Sincethis occurred 3.5 hr after T_(max) for this individual, his data wereincluded in the average analysis for the divided dosing group. Theobservation of 4 and 1 emetic events for the bolus dose and divided dosegroups, respectively, indicates that 7 hr divided dosing gave a lowerincidence of emesis, while providing a therapeutic sertraline dose asevidenced by pharmacokinetic AUC.

Analysis of side effect visual-analogue-scale data was carried out asdescribed in Example 1. Table 2-2 demonstrates that the overall severityof sertraline-induced side effects was lower for the 8 divided dosetreatments.

Thus side effects may be ameliorated by controlling the rate at whichthe sertraline is released into the gastrointestinal tract. Example 2thus demonstrates that delivery at a rate of 200 mg/7 hr=28.6 mg/hr (orslower) results in a decrease in side effect severity (Table 2-2).

Example 2 also demonstrates that sustained release dosage forms whichcontain less than 200 mg sertraline have an advantageous side effectprofile. In the course of carrying out the first half of the example,four 25 mg doses were delivered over 3 hr. with low observed side effectintensity (total dose 100 mg).

As for Example 1, this example also demonstrates that side effects,particularly tremor and dizziness, may be ameliorated by controlling themaximum sertraline concentration in the systemic circulation after oraldosing. In this Example, the 8×25 mg divided dose regimen gave a C_(max)of 46 ng/ml, while the 200 mg bolus dose gave a C_(max) of 75 ng/ml. The8×25 mg divided dose regimen exhibited lower side-effect severity thanthe bolus dose regimen.

TABLE 2-1 Sertraline Pharmacokinetics For A 200 mg Dose given as aSingle Dose, or as Eight 25 mg doses every Hour for 7 Hours (meanvalues). C_(max) T_(max) AUC_(O-last) TREATMENT (ng/ml) (hr) (ng.hr/ml)200 mg 75 5.4 1744 single dose 25 mg per hr 46 10.4 1439 for 7 hr

TABLE 2-2 Mean Cumulative Visual Analog Score Data for Various SideEffects, averaged over all 15 subjects in each group. See test forexplanation of “mean cumulative score”. MEAN CUMULATIVE SCORE GROUP AGROUP B GROUP C SIDE EFFECT (Bolus Dose) (8 Divided Doses) (Placebo)Regurgitation 3.9 0.1 0.1 Dizziness 10.4 4.8 2.1 Tremor 8.9 2.7 0.3

EXAMPLE 3

This example demonstrates that the absorption of sertraline differs whensertraline is dosed directly to various portions of the gastrointestinaltract. Dosage forms which deliver most of their sertraline load beforereaching the transverse or descending colon give higher systemicsertraline exposure than dosage forms which deliver a significantportion of their sertraline load in the transverse or descending colon.

Two groups of 6 volunteers (Groups A and B) each were dosed with 200 mgsertraline or placebo by different four-way crossover regimens. Dosingwas via (1) oral tablets, or (2) infusion of a solution through anasoenteric tube into the stomach, duodenum, or ileocecal region of thesmall intestine, or (3) infusion into the transverse colon via analintubation.

On four different occasions, Group A received (1) oral sertralineimmediate release tablets plus placebo solution infused into thestomach, or (2) oral placebo tablets plus sertraline solution infusedinto the stomach, or (3) oral placebo tablets plus sertraline infusedinto the small intestine at the ileocecal junction, or (4) oral placebotablets plus placebo solution infused into the small intestine at theileocecal junction. On four different occasions, Group B received (1)oral sertraline immediate release tablets plus placebo solution infusedinto the duodenum, or (2) oral placebo tablets plus sertraline solutioninfused into the duodenum, or (3) oral placebo tablets plus sertralineinfused into the transverse colon, or (4) oral placebo tablets plusplacebo solution infused into the transverse colon.

The oral sertraline dose was administered as two 100 mg tablets. Theinfusions were administered as a 2 mg/ml solution at a rate of 20 ml/minfor 5 min.

Blood samples were withdrawn prior to dosing, and at 0.5, 1, 1.5, 2, 4,6, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, 144, 192 and 240 hrpost-dosing. Plasma sertraline concentrations, C_(max), T_(max), and AUCwere also determined as in Example 1. Plasma pharmacokinetic data forthis example are presented in Table 3-1.

Table 3-1 presents the observed average C_(max), T_(max), and AUC forthe various dosing regimens. Infusion into the stomach and duodenalregions gave an AUC (total systemic exposure) which was 79% and 110% ofthe AUC observed after dosing with oral tablets. Thus absorption fromthese regions of the gastrointestinal tract (in addition to more distalregions since the dosed material moved distally with time) was similarto that from oral tablets. Infusion into the ileocecal region of thesmall intestine resulted in an AUC which was 62% of that observed afterdosing oral tablets. Thus the ileocecal region (in addition to moredistal regions) has limited capacity for absorption of sertraline.Infusion into the transverse colon resulted in an AUC which was 16% ofthat observed after dosing oral tables. Thus the transverse (and moredistal descending) colon has a more limited capacity for absorption ofsertraline.

TABLE 3-1 Pharmacokinetics of 200 mg sertraline delivered to variousportions of the gastrointestinal tract. T_(MAX) Dosing Route C_(MAX)(ng/ml) (hr) AUC_(O-LAST) (ng · hr/ml) GROUP A Oral Tablet 39.9 7.01174.5 Stomach Infusion 35.6 7.0 923.1 Ileocecal Infusion 27.3 5.0 727.1GROUP B Oral Tablet 44.7 6.7 1153.4 Duodenal Infusion 48.8 3.7 1270.3Colonic Infusion 10.9 4.4 179.4

EXAMPLE 4

This example illustrates making sustained release sertraline hydrophilicmatrix tablets which release sertraline at different rates depending ontheir composition, size and shape. The processing comprised (1) blendingall components, as designated in Tables 4-1, 4-2 and 4-3, except formagnesium stearate; (2) screening and reblending the same components;(3) adding and blending magnesium stearate; and (4) compressing thefinal blend into tablets.

In batch sizes of 200-350 grams, sertraline hydrochloride was blended ina suitable jar with all other components except magnesium stearate for15 minutes using a Turbula shaker system (Basel, Switzerland). Next, theblend was passed through a 20 mesh screen and shaken again for 15minutes. Then, magnesium stearate was added and the blend was shaken for2 minutes. Using a conventional tabletting press (Manesty F-Press,Manesty Machines, Liverpool, England), the final blend was compressedinto tablets using either ¼ inch by ¾ inch capsular tooling punches forExamples 4A-4M, {fraction (13/32)} inch standard round concave (SRC)punches for Examples 4N and 4O, ¼ inch by ½ inch capsular toolingpunches for Examples 4P-4X, or ¼ inch by {fraction (9/16)} inch capsulartooling punches for Examples 4Y-4AD. A summary of the compositionsmanufactured by direct compression of the formulation blend at 200 mgAsertraline per tablet is shown in Table 4-1 for Examples 4A through 4O,at 100 mg sertraline per tablet is shown in Table 4-2 for Examples 4Pthrough 4X, and at 50 mgA sertraline per tablet is shown in Table 4-3for Examples 4Y through 4AD respectively.

TABLE 4-1 Sustained Release Hydrophilic Matrix Tablet CompositionsManufactured by Direct Compression on the F-Press with Dosage Strengthof 200 mg A/tablet. % % % Tablet Sertraline HPMC HPMC % % % WeightExample Compound* K100LV¹ K4M² Lactose DCP³ MgSt⁴ (mg) 4A 29.8 24.9 5.0— 39.3 1.0 750 4B 29.8 34.9 5.0 — 29.3 1.0 750 4C 29.8 41.6 8.2 — 19.41.0 750 4D 39.8 24.9 5.0 — 29.3 1.0 562 4E 29.8 24.9 5.0 39.3 — 1.0 7504F 29.8 34.9 5.0 29.3 — 1.0 750 4G 29.8 41.6 8.2 19.4 — 1.0 750 4H 39.824.9 5.0 29.3 — 1.0 562 4I 30.0 20.0 10.0 38.0 — 2.0 750 4J 30.0 15.015.0 38.0 — 2.0 750 4K 30.0 50.0 10.0  8.0 — 2.0 750 4L 30.0 33.3 16.718.0 — 2.0 750 4M 30.0 25.0 25.0 18.0 — 2.0 750 4N 39.8 24.9 5.0 — 29.31.0 562 4O 39.8 24.9 5.0 29.3 — 1.0 562 ¹HPMC means hydroxypropylmethylcellulose, Methocel K100LV (Dow Chemical, Midland, MI) ²HPMC meanshydroxypropyl methylcellulose, Methocel K4M (Dow Chemical, Midland, MI)³DCP means dibasic calcium phosphate dihydrate, Emcompress (EdwardMendell Co., Surrey, UK) ⁴MgSt means magnesium stearate *% sertralinecompound reflects quantity of sertraline salt needed to achieve 200 mgA.

TABLE 4-2 Sustained Release Hydrophilic Matrix Tablet CompositionsManufactured by Direct Compression on the F-Press with Dosage Strengthof 100 mg A/tablet. % % % Tablet Sertraline HPMC HPMC % % Weight ExampleCompound* K100LV¹ K4M² Lactose MgSt³ (mg) 4P 30.0 20.0 10.0 38.0 2.0 3754Q 15.0 24.4 12.2 46.4 2.0 750 4R 30.0 15.0 15.0 38.0 2.0 375 4S 15.018.3 18.3 46.4 2.0 750 4T 30.0 33.3 16.7 18.0 2.0 375 4U 15.0 40.6 20.422.0 2.0 750 4V 30.0 26.6 13.4 28.0 2.0 375 4W 15.0 32.5 16.3 34.2 2.0750 4X 15.0 30.5  6.1 46.4 2.0 750 ¹HPMC means hydroxypropylmethylcellulose, Methocel K100LV (Dow Chemical, Midland, MI) ²HPMC meanshydroxypropyl methylcellulose, Methocel K4M (Dow Chemical, Midland, MI)³MgSt means magnesium stearate *% sertraline compound reflects quantityof sertraline salt needed to achieve 200 mg A.

TABLE 4-3 Sustained Release Hydrophilic Matrix Tablet CompositionsManufactured by Direct Compression on the F-Press with Dosage Strengthof 50 mg A/tablet. % % % Tablet Sertraline HPMC HPMC % % Weight ExampleCompound* K100LV¹ K4M² Lactose MgSt³ (mg) 4Y 30.0 20.0 10.0 38.0 2.0  187.5 4Z 15.0 24.4 12.2 46.4 2.0 375 4AA 15.0 18.3 18.3 46.4 2.0 3754AB 15.0 40.6 20.4 22.0 2.0 375 4AC 15.0 32.5 16.3 34.2 2.0 375 4AD 15.030.5  6.1 46.4 2.0 375 ¹HPMC means hydroxypropyl methylcellulose,Methocel K100LV (Dow Chemical, Midland, MI) ²HPMC means hydroxypropylmethylcellulose, Methocel K4M (Dow Chemical, Midland, MI) ³MgSt meansmagnesium stearate *% sertraline compound reflects quantity ofsertraline salt needed to achieve 200 mg A.

EXAMPLE 5

Selected sustained release matrix tablets from Example 4, as shown inTable 5-1, were tested using the in vitro sustained release dissolutiontest procedure with quantification by reverse-phase high performanceliquid chromatography (HPLC) analysis for sertraline to determinesertraline released as a percentage of the total dose, as describedbelow.

Sustained release dosage forms of sertraline were tested in a standardUSP rotting paddle apparatus as disclosed in United States PharmacopeiaXXIII (USP) Dissolution Test Chapter 711, Apparatus 2. Paddle rotationwas set at 50 rpm and the dissolution was conducted in, as the testmedium, 900 mL acetate buffer (0.13M acetic acid) with 0.075M sodiumchloride using potassium hydroxide to adjust pH to 4.0, at 37° C. Thedissolution vessels were covered to prevent evaporation. At indicatedtimes following test initiation (i.e. insertion of the dosage form intothe apparatus vessel), filtered aliquots (typically 2 or 10 mL) from thetest medium were withdrawn and analyzed for sertraline by reverse-phaseHPLC as disclosed below.

Sertraline quantification was conducted by reverse-phase highperformance liquid chromatography as follows. A fixed volume of 20 μLwas injected onto the analytical column (150 mm length×3.9 mm diameterNovaPac C-18 column). The isocratic mobile phase consisted of an aqueousacetate buffer, methanol and acetonitrile in volume percentages of40/15/45. The aqueous acetate buffer was prepared by the following: (1)2.86 mL of glacial acetic acid was added to a 1000 mL Erlenmeyer flaskwith a magnetic stir bar in an ice bath; (2) while stirring, 3.48 mL oftriethylamine was added to the flask; and (3) the flask was filled tovolume and mixed well. To the aqueous acetate buffer (40%) was addedHPLC-grade methanol (15% v/v) and HPLC-grade acetonitrile (45% v/v).After mixing well, the mobile phase was vacuum filtered and degassedusing a 0.45 μm PTFE filter (Lid-X 305 disposable solid liquidseparators). The mobile phase flow rate was 1.8 mL/min with sertralineUV detection at 254 nm.

Dissolution results reported as the percent of sertraline dissolvedversus time are presented in Table 5-1 (n=3 tablets). Examples 4P, 4Q,4V, 4X, 4Z, 4AB, 4AC, and 4AD satisfied the dissolution criteria and aresustained release embodiments of this invention. The other formationsfrom Tables 4-1, 4-2 and 4-3 were not tested, but are also sustainedrelease embodiments of this invention.

TABLE 5-1 In Vitro Sertraline Sustained Release from hydrophilic MatrixTablet Compositions Designated in Table 4-1, 4-2 and 4-3 Example Q₁ (%)Q₄ (%) Q₈ (%) Q₁₂ (%) Q₁₆ (%) Q₂₄ (%) 4P 13.2 26.6 41.4 56.1 70.0 89.74Q 9.6 20.4 32.4 47.8 60.2 75.2 4V 6.3 20.9 40.2 54.0 65.1 82.1 4X 8.924.8 44.1 61.3 73.7 92.2 4Z 11.3 25.8 43.0 59.0 73.3 88.4 4AB 5.0 16.428.7 40.4 51.9 70.7 4AC 5.7 19.6 37.3 54.9 70.4 92.2 4AD 9.6 28.5 52.072.4 86.2 96.8 Q = reported values of % drug released represents theaverage of 3 tablets

EXAMPLE 6

This example demonstrates that certain sertraline side effects (e.g.nausea, regurgitation, and diarrhea) are partially or primarily mediatedby direct contact of orally dosed sertraline with the uppergastrointestinal tract, rather than mediated by the presence ofsertraline in the systemic circulation after absorption. Bypassing thestomach by dosing sertraline orally in a dosage form which exhibitsdelayed release before sustained release (i.e., a delayed plus sustainedrelease dosage form) can thus further ameliorate the locally mediatedside effects of sertraline.

In a subset of a larger double-blind, randomized, placebo-controlledparallel group study, healthy male human subjects were divided into twogroups (Study I). Group A received a single 200 mg sertraline dose astwo 100 mg sertraline tablets (Zoloft commercial 100 mg tablets) (“bolusdosing” group). The tablets were administered with 50 ml water. Group Breceived two placebo tablets. All subjects were dosed after an overnightfast.

Blood samples were withdrawn prior to dosing, and at 0.5, 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24, 36, 48, 72, 96,120, 144, 168, 192, and 240 hr post-dosing. Plasma sertralineconcentrations were determined using capillary gas chromatography. Totalsystemic exposure to sertraline was determined by measuring the areaunder the plasma sertraline concentration vs. time curve (AUC) for eachsubject in a given group, and then by calculating a mean AUC for thegroup. C_(max) is the maximum observed plasma sertraline concentrationachieved in a subject. T_(max) is the time at which C_(max) is achieved.After the 200 mg sertraline dose, average C_(max) was 74 ng/ml, averageT_(max) was 6 hr, and average AUC was 1646 ng-hr/ml (averaged for 15subjects).

A similar second study was carried out (Study II). After the 200 mgsertraline dose, average C_(max) was 75 ng/ml, average T_(max) was 5.4hr, and average AUC was 1744 ng-hr/ml (averaged for 11 subjects). Foursubjects in the 200 mg dose group had emesis at 2.6, 2.8, 2.8, and 3.8hr. The data from these four subjects were not included in thepharmacokinetic averages.

Prior to dosing and each blood sampling time, each subject filled out aquestionnaire, which consisted of a series of “Visual Analogue Scales”in which the subject was required to rate, on a scale of 0-10, theseverity of certain potent side effects. The subjects were instructedthat “0” indicated an absent effect and “10” indicated the worstpossible effect. The subjects were instructed to interpolate between 0and 10 for moderate side effects.

A total of 30 subjects completed Study I: 15 each in Groups A and B. Foreach side effect evaluated at 30 time points, a total of 900 individualvisual-analogue-scale evaluations were obtained. A total of 29 subjectscompleted Study II: 14 in Group A and 15 in Group B. For each sideeffect evaluated at 30 time points, a total of 870 individualvisual-analogue-scale evaluations were obtained.

FIG. 6 presents the relationship between plasma sertraline concentrationand average self-reported visual analogue score for nausea in Study I.This plot, known as a pharmacokinetic-pharmacodynamic relationship plot(“PK/PD Plot”), was obtained as follows. For the 15 subjects in Group A,plasma sertraline concentration was averaged at each blood collectiontimepoint, to give an average sertraline concentration for Group A ateach time point. Likewise, for the 15 subjects in Group A, the visualanalogue score for nausea was averaged at each time point. The averagenausea scores at each time point (y-axis) were potted vs. sertralineplasma levels at the corresponding time point (x-axis). The arrow on theplot demonstrates the progression of the PK/PD relationship as timeprogressed. The PK/PD plot of FIG. 6 exhibits “clockwise hysteresis” forthe 200 mg bolus dose. Thus as time progressed, the nausea score and theplasma sertraline concentration both increased until the nausea scorereached a maximum value, at a plasma sertraline concentration which wasbelow the maximum plasma sertraline concentration C_(max). As C_(max)was reached (at ˜70 ng/ml), the nausea score fell to a lower value. Asthe subsequent plasma sertraline concentrations fell, the nausea scoreassumed values which were lower than the scores observed for the sameplasma sertraline concentrations at earlier timepoints. This “clockwisehysteresis” (or “proteresis”) is consistent with the interpretation thatsertraline induced nausea is significantly mediated by direct contact ofsertraline with the GI tract, and is not entirely mediated by thepresence of sertraline in the systemic blood, since the average nauseascore is not monotonically related to plasma sertraline concentration.At early time points after dosing (0-3 hr), orally dosed sertraline isprimarily in contact with the stomach. Since nausea is not directlymonotonically related to plasma sertraline concentration, and isapparently primarily mediated by contact with the gastrointestinaltract, releasing sertraline lower in the gastrointestinal tract, e.g.the duodenum or jejunum, will result in decreased contact time with theupper gastrointestinal wall, and thus less nausea.

In Study 1, diarrhea was also shown to exhibit clockwise hysteresis inits side effect score vs. plasma sertraline concentration curve. Themaximum diarrhea score was reached at 3 hr post-dose, long before theobserved average plasma T_(max) of 6 hr in these subjects. Thus delayingthe release of orally dosed sertraline until the stomach is passed mayresult in less diarrhea.

As described above, in Study 2, four subjects exhibited regurgitation.Individual PK/PD plots for these subjects, for the side effectregurgitation, exhibited clockwise hysteresis. Thus delaying the releaseof orally dosed sertraline until the stomach is passed may result inless regurgitation.

EXAMPLE 7

This example illustrates a process for making sustained releasesertraline multiparticulates according to the invention. The process formaking sustained release sertraline multiparticulates consisted ofpreparing uncoated sertraline multiparticulate cores by rotarygranulating with microcrystalline cellulose as spheronizing agent andwater as a granulating agent until a mean granule size of >1 mm wasachieved.

Sertraline multiparticulates were prepared using a fluid bed processorwith rotor insert (Glatt GPCG-1 by Glatt Air Techniques, Ramsey, N.J.).The rotor bowl was charged with 300 grams of sertraline drug and 300grams of microcrystalline cellulose as spheronizing agent. Then, waterwas tangentially sprayed into the rotating bed of drug andmicrocrystalline cellulose until the agglomeration endpoint (defined bythe mean granule size) was reached. After the granulation was completed,the multiparticulates were dried in the rotary fluid bed until theirwater content was less than 2% (measured by weight loss on drying orLOD). The composition and key process parameters of thesemultiparticulates are listed in Table 7-1.

TABLE 7-1 Sustained Release Sertraline Multiparticulate Composition andKey Manufacturing Parameters Employed During Rotary GranulationProcessing Rotor Spray Endpt Mean Example Sertraline* Avicel Water SpeedRate LOD Granule No. (grams) (grams) (grams) (rpm) (g/min) (% H2O) Size(μm) 7A 300 300 1100 640 15-20 49 1200 *sertraline quantities in termsof hydrochloride salt form

EXAMPLE 8

This example illustrates a process for making sustained releasesertraline multiparticulates according to the invention that release atdifferent rates depending on the thickness of the sustained-releasecoating. The process comprises (1) preparing uncoated sertralinemultiparticulate cores by rotary granulating with or withoutmicrocrystalline cellulose as a granulating agent and water or a bindersolution; and (2) applying a rate-limiting coating over the cores. Thisexample further evaluates the release profile of the sustained releasemultiparticulates.

Sertraline multiparticulates were prepared using a fluid bed processorwith rotor insert (Glatt GPCG-1 by Glatt Air Techniques, Ramsey, N.J.).The rotor bowl was charged with 300-500 grams of sertraline drug and0-500 grams of microcrystalline cellulose as spheronizing agent. Water,plasticized hydroxypropyl methylcellulose (Opadry™) orpolyvinylpyrrolidone (Povidone C15) binder solution (10% solidsconcentration) was tangentially sprayed into the rotating bed until theagglomeration endpoint (defined by the mean granule size) was reached.The target mean granule size was varied from 100 to 1400 μm during themanufacturing of these formulations. After the granulation wascompleted, the final multiparticulates were dried in the rotary fluidbed until their moisture content was less than 2% (measured by loss ondrying, LOD). A summary of the compositions of multiparticulatesmanufactured using water as the granulating agent are detailed in Table8-1 for Examples 8A through 8F. A summary of the multiparticulate corecompositions, manufacturing parameters and final mean granule sizeproduced during the manufacture of the formulations that utilized abinder solution consisting of either an aqueous Opadry or Povidonesolution as granulating agent are shown in Table 8-2 for Examples 8G-8S.

TABLE 8-1 Sertraline Multiparticulate Core Compositions andManufacturing Parameters Employed During Rotary Granulation ProcessingUsing Water as Granulating Agent Rotor Spray Endpt Mean ExampleSertraline Avicel Water Speed Rate LOD^((b)) Granule No (grams) (grams)(grams) (rpm) (g/min) (% H2O) Size (μm) 8A 300 300 1340 640 13 39 320 8B300 300 1340 640 12 41 470 8C 500 500 2950 640- 13-15 42 465 585 8D 335165  630 630 14 36 510 8E  300^((a)) 300  700 630 13 37 370 8F 300 3001060 630 12 45 600 ^((a))jet milled sertraline hydrochloride <10 μm^((b))LOD - Loss on drying

TABLE 8-2 Sertraline Multiparticulate Core Compositions andManufacturing Parameters Employed During Rotary Granulation ProcessingUsing a Binder Solution as Granulating Agent. Mean Rotor Spray OutletAir Granule Example Sertraline Avicel Binder Speed Rate Temp VelocitySize No (grams) (grams) (10%) (rpm) (g/min) (° C.) (Pa) (μm) 8G 500 0 OC640 5-15 33 10-14 530 8H 500 0 OC 640 5 34 10 130 8I 500 0 OC 640 5 3210 205 8J 500 0 OC 640 10 27 12 270 8K 400 100 OC 640 15 30 13 320 8L375 125 OC 800 26 31 20 680 8M 375 125 OC 810 21 37 10 340 8N 375 125PVP 800 25 33 8 n.d. 8O 375 125 OC 855 24 36 8 1400 8P 375 125 OC 855 2537 8 390 8Q 375 125 OC 855 24 36 10 510 8R 375 125 OC 855 24 37 12 3608S 375 125 OC 855 24 36 11 430 OC means Opadry ™ Clear, plasticizedhydroxypropyl methylcellulose PVP means Povidone C15, plasticizedpolyvinylpyrrolidone

Next, the sertraline multiparticulate core granules (Example 8D) werespray coated with a rate-limiting coating in the rotary fluid bed (GlattGPCG-1, Glatt Air Techniques, Ramsey, N.J.) until the desired end point(coating weight %) was achieved. In this example, the rate-limitingcoating was composed of plasticized ethylcellulose (Surelease™)suspension diluted to 25% solids and hydroxypropyl methylcellulose(Opadry™, Colorcon, Inc.) in weight ratios of 85% Surelease™ to 15%Opadry™. This coating was applied to the multiparticulate core granulesmanufactured according to this Example to coating levels ranging from 5wt % to 25 wt %.

EXAMPLE 9

This example illustrates the process for making a sustained releasesertraline non-erodible matrix tablet. The processing comprises of (1)blending all components except for magnesium stearate; (2) screening andreblending the same components; (3) adding and blending magnesiumstearate; and (4) compressing the final blend into tablets. This examplefurther evaluates the in vito release profile of sertraline from thematrix tablets using the in vito test described in the specifications.

In a batch size of 100 grams, sertraline was blended in a suitable jarwith all other components except magnesium stearate for 10 minutes us aTurbula shaker system (Base, Switzerland). Next, the blend was passedthrough a 40 mesh screen and reblended for 5 minutes. Then, magnesiumstearate was added to the mixture and blended for 5 minutes. Using theManesty F-Press (Manesty Machines, Liverpool, England), the final blendwas compressed into tablets using conical tablet tooling punches withtop-to-base diameter ratio of 1:3 and heigh-to-base ratio of 2:5. Asummary of the composition manufactured by direct compression of theformulation blend at 127 mgA sertraline per tablet is shown in Table9-1.

TABLE 9-1 Sustained Release Non-erodible Matrix Tablet CompositionManufactured by Direct Compression on the F-Press with Dosage Strengthof 127 mgA/tablet % Sertraline Compound* % Ethocel¹ % Lactose % MgStTablet Weight (mg) 33.7 40.0 24.3 2.0 420 ¹Ethocel ™, Ethylcellulose NFStandard Premium, viscosity 10, Dow Chemical *sertraline compoundquantities in terms of hydrochloride salt form

Finished sustained release non-erodible matrix tablets were tested usingthe in vitro sustained release dosage test procedure described inExample 5. The results are presented in Table 2 (n=1 tablet). Thisnon-erodible matrix tablet satisfies the dissolution criteria and is asustained release embodiment of this invention.

TABLE 9-2 In Vitro Sertraline Sustained Release from Non-erodible MatrixTablet Composition Designated in Table 9-1 into 900 mL 0.13 M acetatebuffer with 0.075 M sodium chloride, pH 4.0 at 37° C. in USP Apparatus#2 with Paddle Speed Setting of 50 rpm Q₁ Q₄ Q₈ Q₁₂ Q₁₆ Q₂₄ ReleaseRate^(†) (%) (%) (%) (%) (%) (%) (mgA/hr) 6.2 13.9 23.1 28.5 33.8 41.22.2 Q = reported values of % drug released represents one tablet.^(†)means that sertraline release rate was calculated based on the 24 hrtimepoint because 80% release did not occur within the 24 hr testingperiod.

EXAMPLE 10

This example illustrates that organic acids have the ability to raisethe solubility of the hydrochloride salt of sertraline. The acids werescreened by dissolving the candidate add in water and then stirringexcess sertraline hydrochloride in the acid solution for at least 8hours. The concentration of sertraline in the supernatant was thenmeasured by HPLC analysis. The results of this test are listed in Table10-1, below. Most of the acids listed in the table successfully raisedthe solubility of sertraline hydrochloride (normal solubility 25 mg/ml).

TABLE 10-1 Approximate Excipient Excipient Concentration (mg/ml)Sertraline Solubility (mg/ml) D,L-malic acid 900 21 Citric acid 600 20Erythorbic acid 400 19 Adipic acid  14 12 Maleic acid 700 6.4 L-asparticacid  10 5.5 Tartaric acid 1400  5.5 L-glutamic acid  12 5.4 Fumaricacid  11 3.1 Tannic acid 2000  2.8 D,L-tyrosine 600 2.2

Preferred acids, based on this screening test, are malic, citric,erythorbic, and adipic acids. Mateic, L-aspartic, tarlaric, andL-glutamic acids also significantly improved sertraline hydrochloridesolubility. Some controlled-release dosage forms with such acids in thecore will perform better than those without such acids. This isparticularly true for osmotic-based formulations that deliver a solutionof drug.

EXAMPLE 11

This example illustrates that organic acids have the ability to raisethe solubility of the acetate salt of Sertraline by a method similar tothat used for the hydrochloride salt described in Example 10. Theexcipient excipient concentration, and sertraline solubility are listedin Table 11-1 below. Based on these results, preferred acids to includein a dosage form where increased Sertraline acetate solubility isdesired are ascorbic, erythorbic, citric, lactic, aspartic, glutamic,and aconitic acids.

TABLE 11-1 Excipient Concentration Sertraline Solubility Excipient(mg/ml) (mg/ml) Ascorbic acid 400 >425   Erythorbic acid 400 >330  Citric acid 600 146 Lactic acid 213 >294   Aspartic acid  7 110 Glutamicacid  12 108 Aconitic acid 500  >92   Itaconic acid 150  72 Succinicacid  77  28 None —  64

EXAMPLE 12

This example illustrates that organic acids and three calcium salts havethe ability to raise the aqueous solubility of the lactate salt ofsertraline using a method similar to that used for the hydrochloridesalt described in Example 10. The excipient, the excipient concentrationin the aqueous test solution, and the Sertraline lactate solubility inthe test solution are listed in Table 12-1 below. Solubility ofSertraline lactate in water is approximately 125 mg/ml. The data belowshow that eight organic solutions had sertraline lactate solubilities ofabout the same or higher than 125 mg/ml; adipic, erythorbic, itaconic,citric, aspartic, glutamic, histidine, and ascorbic. Also, a solution ofa mixture of two of these acids also had high solubility; ascorbic andaspartic Sertraline lactate solubility was also high in calcium saltsolutions, either alone (calcium citrate) or mixed with ascorbic acid.

TABLE 12-1 Excipient Concentration Sertraline Lactate Excipient (mg/ml)Solubility (mg/ml) Adipic acid  14 360 Erythorbic acid 400 >217  Itaconic acid 150 >202   Citric acid 600 162 Aspartic acid  7 >155  Glutamic acid  12 >125   Histidine  42 >116   Ascorbic/Aspartic 400/7  116 Ascorbic 400 102 Glycine 250  66 Aconitic acid 200  <59   Tartaricacid 1400   12 Fumaric acid  11  <9   Sorbic acid  3  <9   Calciumlactate/ 50/400 160 Ascorbic acid Calcium citrate  10 165 Calciumcarbonate/ 50/400 176 Ascorbic acid None — 125

EXAMPLE 13

The lower solubility of the sertraline chloride salt and of allsertraline lactate and sertraline acetate salts in the presence of highchloride concentrations suggest that core formulations are preferred forwhich sertraline stays in solution that is, it does not precipitate orform a gel-like material when chloride is present. Certain organic acidsand salts were found to inhibit precipitation or gelation of Sertralinewhen chloride is present via the following screening test. Sertralinelactate was dissolved in water either alone (as a control) or with acandidate excipient. Sodium chloride was then added (as a concentratedsolution) and the result observed. An excipient was consideredbeneficial if the solution remained clear and fluid. The more chloridethat could be added to an excipient solution with the solution remainingclear, the more beneficial was the excipient. Table 13-1 below shows theresults of this screening test, indicating that all the excipientstested increased sertraline concentration in the chloride solutions.

TABLE 13-1 Excipient Concen- Concen- tration Final Sertraline trationNaCl Concentration Observation After Excipient (mg/ml) (mM) (mg/ml) NaClAddition None —  38  22 gel/precipitate Ascorbic/ 400/7  152 162solution Aspartic acids Aspartic acid 7 114 162 solution 7 152 100 gelAscorbic acid 400  100 102 precipitate Ascorbic acid/ 400/50 150 165solution calcium lactate Ascorbic acid/ 400/50 150 170 slightly turbidcalcium carbonate Citric acid/ 600/50 150 162 solution calcium lactateHistidine 42  150 110 slight precipitate

EXAMPLE 14

Organic compounds (solubilizers) were screened for their ability toenhance the solubility of sertraline lactate in aqueous with or withoutthe presence of chloride. Excess sertraline lactate was added to anaqueous solution of the candidate solubilizer and, in most cases anorganic acid. The organic acids were saturated in these solutions andthe additional solubizing agents were at the concentration shown inTable 14-1. The equilibrium sertraline solubility was measured. Then,sodium chloride was added to the saturated solution and the finalsertraline concentration was measured. The results of these screeningtests are summarized in Table 14-1.

TABLE 14-1 Solubilizer Sertraline NaCl Sertraline Concentration OrganicSolubility Concentration Concentration Solubilizer (mg/ml) Acid (mg/ml)(mM) (with NaCl) 1 None (control) — none 125 150 5 27 Monocaprylin 10ascorbic 160 150 160 3 Triacetin 100 ascorbic 170 150 170 4 Monobutyrin50 none 120 150 120 5 Diacetin 50 ascorbic 120 150 120 6 Imwitor ® 31210 ascorbic 120 150 120 7 Imwitor ® 375 10 ascorbic 120 150 120 8Imwitor ® 742 50 none 120 150 120 9 Imwitor ® 988 50 none 140 100 140 10Triethyl citrate 50 ascorbic 160 150 160 11 Pluronic ® L31 50 none 120100 120 12 Cremophore EL 50 ascorbic 120 150 120 13 Sucrose acetate 50ascorbic  120* 150 120 isobutyrate 14 Sodium capryl lactate 50 ascorbic120 150 120 15 Sucrose monolaurate 50 none 150 150 150 16 Sodium lauryllactate 50 ascorbic 120 150 120 17 Span ® 80 50 ascorbic 120 150 120

EXAMPLE 15

This example illustrates that solubilizers for sertraline also canincrease the rate of dissolution of sertraline. The effect of acandidate excipient on sertraline dissolution rate was determined byadding solid drug, the candidate solubilizing excipient, and, in somecases, other excipients such as an organic acid and an osmagent (such asa sugar) to a 1.8 ml centrifuge tube. The sample tubes were spun at 14KG for 5 minutes in a microcentrifuge to pack the powder. 150 μl gastricbuffer was added to the packed powder and the samples were gentlyagitated,then spun at 14K G in a microcentrifuge for 2 minutes. Thesamples were then removed from the microcentrifuge and allowed to standundisturbed until the solution was removed. The solution was removedfrom the samples after a total of 10 minutes after gastric buffer wasadded to the powder pack, and analyzed by HPLC to determine thesertraline concentration.

The dissolution rate (mg sertraline/ml-min) was calculated from themeasured concentration on of dissolved sertraline in the supernatant asa function of time over the first 10 minutes of dissolution. Thesedissolution rates and the excipient mixtures for which they weremeasured are summarized in Table 15-1 below. As shown, several excipientmixtures containing solubilizers significantly (about 3× or greater)increased the dissolution rate of sertraline, compared with sertralinealone and compared with sertraline and ascorbic acid.

TABLE 15-1 Sertraline Candidate Excipient Organic Other SertralineDissolution Concen- Organic Acid Conc. Osmagent Other Excipient SaltForm Rate (mg/ml- Name tration (wt %) Acid (wt %) Osmagent Conc. (wt %)Excipient Conc. (wt %) Conc. (wt %) min) None — none — none — none —lactate 0.9 100  None — ascorbic 51.0 lactose 20 none — lactate 3.5 14Imwitor ® 312 5.0 ascorbic 49.5 lactose 12.5 CaCO₃ 5 lactate 20.9 14Lecithin 5.0 ascorbic 51.0 lactose 15 none — lactate 10 14 PEG 3550 5.0ascorbic 51.0 lactose 15 none — lactate 9.3 14 Capmul ® MCM 5.0 ascorbic71.0 none — none — lactate 14.5 24 Capmul ® MCM 4.7 none none lactose 17CaCO₃ 4.7 lactate 4.3 Ca citrate 47   13.1 Imwitor ® 191 5.0 ascorbic49.5 lactose 12.5 CaCO₃ 1.0 lactate 8.0 14 Myrerol ® (18-99) 5.0ascorbic 49.5 lactose 12.5 none — lactate 6.4 14 Span ® 60 5.0 ascorbic51.0 lactose 15 none — lactate 9.5 14 Ascorbyl 6.8 none none lactose74.2 none — lactate 4.3 palmitate 19 Methyl paraben/ 0.5/0.5/1.0ascorbic 50.0 lactose 17.5 none — lactate 11.5 propyl paraben/ 14 propylgallate Imwitor ® 312 6.8 aspartic 74.2 none — none — lactate 5.3 19

EXAMPLE 16

This examples illustrates a method for making osmotic tablets comprisinga tablet core containing sertraline surrounded by a semipermeableasymmetric membrane coating. Sertraline-hydrochloride was triturated byhand for 10 minutes with citric acid and microcrystalline cellulose(Avicel PH 102, FMC) using a 6½ inch diameter mortar and pestle.Magnesium stearate was then blended in as a lubricant by sting with aspatula for 60 seconds. The weight ratio of Sertraline-hydrochloride tocitric acid to microcrystaline cellulose to magnesium stearate was8.5:63.8:23.7:4; with a total weight of 10 grams. The blended mixturewas pressed into 470 mg tablets in a modified hydraulic jack(manufactured by Dayton) fitted with a pressure gauge and ⅜ inch concavepunch under 2500 PSI pressure for 2 seconds. The dimensions of theresulting tablets were ⅜ inch in diameter and ¼ inch thick. Asemipermeable membrane coating (as described in U.S. patent applicationNo. 397,974, allowed Oct. 6, 1996, entitled The Use of AsymmeticMembranes in Delivery Devices) was applied to these tablets using aLDCS-20 pan coater (Vector Corp.) at a spray rate of 20 grams perminute, an inlet temperature of 40C and air flow of 40 cfm. The coatingsolution contained by weight 10% Cellulose acetate, (Eastman Chemical,CA398-10), 2.5% polyethylene glycol (BASF, PEG 3350), 15% water and72.5% acetone. The coated tablets were dried 1 hour at 50C beforetesting. After drying, the weight of applied coating material was 15.4%of the total weight. These tablets contained a sertraline dose of 50mgA/tablet.

EXAMPLE 17

Osmotic delivery tablets were prepared by using essentially the sameprocedure for making the tablet cores and applying the asymmetricmembrane coating to the cores described in Example 16. The compositionof the cores and coating solution varied from that used in Example 16 asshown in Table 17-1. Example 16 is listed in Table 17-1 for comparison.Significant core compositional changes shown include: the Sertralinesalt form, the type and amount of solubilizer, and the type and amountof osmagent. The amount of binder (Avicel) lubricant (magnesiumstearate), and solubilizer were varied as necessary to obtain goodtableting and wetting properties. These tablets contained a sertralinedose of 50 mgA/tablet.

TABLE 17-1 Osmotic Coating Solution Ex- Core Composition Coating am-Core Drug Poly- Poly- Wa- Weight ple Weight Salt Acid SolubilizerOsmogent Avicel Mg St. mer mer PEG ter (dry No. (mg) Form Wt % Type Wt %Type Wt % Type Wt % wt % wt % Other Type wt % wt % wt % wt %) 16 470chloride 12 none none lactose 66 20 2 none CA 10 2.5 15 15.4 17a 470lactate 14 none none lactose 65.4 19.3 1.33 none EC 6 4 8 1 17b 470acetate 14 ascorbic 50 none lactose 20 15 none Myrj EC 6 4 10 10.1 17c470 lactate 14 ascorbic 50 none lactose 15 21 none none EC 6 4 10 10.117d 470 lactate 14 citric 50 none lactose 20 15 none Tween EC 6 4 10 9.917e 470 lactate 14 aspartic 11 none fructose 38 29.5 2.5 Ca CA 10 2.5 1511 Acetate 17f 470 lactate 14 none Im 5 lactose 58.4 20 2.6 none EC 6 410 10 17g 470 lactate 14 none Im 5 xylitol 53.5 25 2.5 none CA 10 2.5 1515.5 17h 470 lactate 14 ascorbic 50 MC 5 lactose 12.5 12.5 none Myrj EC6 4 10 10.5 17i 470 lactate 14 glu- 10 MC 5 sucrose 50 15 none Ca EC 6 410 10.5 tamic lactate, Myrj 17j 470 lactate 14 aspartic 11 MC 5 sucrose53 15 Myrj EC 6 4 10 10.1 17k 470 lactate 14 ascorbic 32 Im 5 lactose 1229 3 CaCO₃ EC 7 3 6 15.1 17l 470 lactate 14 ascorbic 32 Im 5 lactose 1229.5 2.6 CaCO₃ EC 6 4 10 10.1 17m 470 lactate 14 aspartic 11 Im 5fructose 36 27 2.5 Ca CA 10 2.5 15 10.3 acetate 17n 470 lactate 14glycine 25 Im 5 fructose 28.6 25 2.5 none CA 10 2.5 15 15.9 17o 560lactate 11.2 ascorbic 36.5 Tri- 4.2 lactose 16.2 31.1 none Myrj EC 6 410 10 acetin 17p 470.5 lactate 13.9 succinic 37.2 PEG 15.9 lactose 37.9none none Klucel, EC 6 4 10 10 SLS 17q 536 lactate 12.1 ascorbic 44Capmul 4.4 lactose 12 22.1 1.5 CaCO₃ EC 6 4 10 9.9 17r 470 lactate 14ascorbic 37 Span 60 5 lactose 11.4 25 2.6 CaCO₃ EC 6 4 10 9.5 17s 470lactate 14 ascorbic 37 Lecithin 5 lactose 11.4 25 2.6 CaCO₃ EC 6 4 109.9 17t 470 lactate 14 ascorbic 32 Im 5 lactose 12 29.5 2.7 CaCO₃ EC 7 36 17 17u 470 lactate 14 ascorbic 32 Im 5 lactose 12 29.5 2.7 CaCO₃ EC 64 8 15 17v 470 lactate 14 aspartic 11 Im 5 fructose 35 27 2.5 Ca CA 102.5 15 20 acetate 17w 470 lactate 14 aspartic 11 none fructose 38 29.52.5 Ca CA 10 2.5 15 10 acetate IM = Imwitor 312 Capmul = Capmul MCMTween = Tween 80 CA = cellulose acetate 398-10 MC = monocaprylin Mg St.= magnesium stearate Klucel = Klucel EF EC = Ethocel S-100 PEG =polyethylene glycol 3350 Myrj = Myrj 52 SLS = sodium lauryl sulfate

EXAMPLE 18

The rates of release of Sertraline from selected formulations describedin Examples 16 and 17 were determined according to the proceduresdescribed in Example 5 with the exceptions that 750 ml of solution wasused in the dissolution apparatus and the stirring speed was 100 rpm.Analysis of Sertraline released was determined by reverse-phasehigh-performance liquid chromatography (RP HPLC).

The results of release-rate tests performed using these procedures arelisted in Table 18-1. The first two formulations listed, 18a and 18b(formulations 16 and 17a), show release rates lower than claimed in thisinvention and are included as comparison examples. Both of theseformulations contain a sertraline salt (hydrochloride or lactate) andonly lactose as the osmagent and no solubilizing excipients.Formulations 18c, 18e, and 18h listed in Table 18-1 all contain asolubilizing excipient and all demonstrate sustained release ofsertraline and are embodiments of this invention. Formulations 18d, 18f,and 18g are delayed plus sustained release embodiments of thisinvention. Likewise the remaining formulations in example 17 (17 b-w)are also sertraline formulations that are embodiments of this invention.

TABLE 18-1 Sertraline Tablets of Release Example Fraction of DrugReleased (%) At Specified Time Test No No 0 Hr 1 Hr 2 Hr 4 Hr 8 Hr 12 Hr20 Hr 18a 16 0 0 0 0 0 0 0 18b 17a 0 0 1 2 — 10 12 (17 hr) 18c 17e 0 615 35 62 76 78 18d 17j 0 0 0 4 19 28 44 18e 17m 0 8 19 37 60 73 83 18f17n 0 0.7 6 17 37 54 78 18g 17v 0 0.4 4 13 31 41 53 18h 17w 0 8 18 38 5664 66

EXAMPLE 19

This example illustrates osmotic-based sertraline tablets that consistof an inner core containing an osmagent and solubilizing excipientsurrounded by a sertraline and excipient layer and then surrounded by asemipermeable coating. The tablets of this example varied from the otherexamples in that an inner core containing acid, binder and solubilizerwas made, tableted, and placed inside a larger drug containing tablet.Citric acid and microcrystalline cellulose (Avicel, PH 102, FMC) weretriturated by for 5 minutes using a 4½ inch diameter mortar and pestle.Polyoxyethylene 40 monostearate (Myrj 52, BASF) was then added andtriturated for 1 minute. The weight ratio of citric acid tomicrocrystalline cellulose to Myrj was 86.1:9.8:4.1, with a total weightof 4 grams. The blended mixture was pressed into 232 mg tablets as inExample 16 except that the tablet punch was ¼ inch. The resulting tabletcore was ¼ inch in diameter and ¼-inch thick. The blend for the outertablet was prepared like Example 17. It contained sertraline lactate,citric acid, lactose. Avicel, and polyoxyethylene sorbitan (Tween 80,ICI) in a weight ratio of 14:50:20:15:1. The final tablet was made byplacing 200 mg of the drug containing blend into the bottom of thestandard ⅜-inch die then the 232-mg citric add tablet was placed on topof this and an additional 270 mg of the drug containing blend pouredonto the top. The tablet was then pressed using the same conditions asin Example 16. The dimensions of the resulting tablet were ⅜ inch indiameter by ½-inch thick. A semipermeable membrane coating was appliedto the tablets using the same method as in Example 16. Results fromrelease rate tests similar to those described in Example 5 indicate thatthis osmotic formulation of sertraline is an embodiment of thisinvention.

EXAMPLE 20

This example illustrates a method for making an osmotic tabletconsisting of a bilayer tablet core surrounded by a semipermeablecoating. To form the drug containing granulation the following materialsare blended and wet granulated in a mixer: 50 to 200 g sertraline andits pharmaceutically acceptable salts; from 250 to 325 g of polyethyleneoxide having a molecular weight of about 100,000 and from 0 to 275 g ofa polyethylene oxide having a molecular weight of about 200,000, from 10to 30 g of a hydroxypropylmethylcellulose having an average molecularweight of about 11,300; and from 0 to 10 mg of a magnesium stearate. Thesecond granulation to make the second layer in the tablet core comprisesfrom about 110 to 140 g of a polyethylene oxides having an averagemolecular weight ranging from about 5,000,000 to 7,500,000; from 5 to 25g of a hydroxypropylmethylcellulose having an average molecular weightof about 11,300; from 40 to 70 g of sucrose; and, from 0 to 10 g ofmagnesium stearate. These granulations are used to make a bilayer tabletcore with one layer containing sertraline and the second layer mostlyswellable hydrophilic materials. These bilayer tablets are then coatedwith a semipermeable coating comprising 70% to 98% cellulose acetatehaving an acetyl content of 32% to 39.8%, and from 2 to 30% ofpolyethylene glycol having an average molecular weight of about 3350. Inthe coating at least one exit passageway is formed on thesertraline-containing side of the tablet.

EXAMPLE 21

Osmotic delivery tablets were prepared with a water permeable outercoating through which were drilled delivery ports for the passage ofsertraline dissolved in the aqueous solution containing the tablet core.Tablet cores composed of 14.0 wt % sertraline lactate, 11.0 wt %aspartic acid, 47.4 wt % sucrose, 25.0 wt % Avicel PH 101, and 2.6 wt%magnesium stearate (total core weight was 470 mg) were prepared byessentially the same method given in Example 17. These tablet cores werethen coated with a solution composed of 6% ethylcellulose (EthocelS-100, Dow Chemical), 4 wt % polyethylene glycol (PEG 3350, BASF) and 8wt % water in acetone using the method described in Example 17 such thatthe coming weight was 70.4 mg per tablet (total coated tablet weight was540.4 mg). For some of the tablets, 3 holes, each 340 μm in diameter,were drilled in each face of each tablet (total of 6 holes per tablet).For a second set of tablets, 18 holes, each 340 μm in diameter, weredrilled in each face of each tablet (total of 36 holes per tablet).

A tablet of each type was each tested for sertraline release using 0.75L of acetate/saline buffer as described in Example 5. The percentsertraline released to the receptor solution as a function of time foreach type of tablet is shown in Table 21-1, below. Both types of tabletsshowed similar release profiles, indicating that release of drug ispredominately osmoically driven, (if rlease was predominatelydiffusional, the tablets with 36 holes should release drug approximately6 times faster than the tablets with 6 holes).

TABLE 21-1 Time Sertraline Released (%) (hr) 6-Hole Tablet 36-HoleTablet 0  0  0 1  3  7 2 12 17 4 26 32 8 44 44 12  47 46

EXAMPLE 22

This example describes swelling hydrogel controlled release sertralinetablets. Sertraline hydrochloride or acetate or lactate or aspartate (50mgA sertraline) is blended with 20K molecular weight polyethylene oxide(PEO-20K) (350 mg) with other solubilizers and excipients, and the blendis tabletted on a Manesty Type-F3-press. The tablets are spray-coatedwith a solution of cellulose acetate in acetone/ethanol, to a final dryweight coating of 14% of the total coated tablet weight A 2 mm diameterhole is drilled (via mechanical, laser or other means) through thecoating on one face of a portion of the tablets. A 2 mm diameter hole isdrilled through the entire center of the tablet for another portion ofthe tablet.

EXAMPLE 23

This example describes swelling hydrogel controlled release sertralinetablets. Sertraline hydrochloride or acetate or lactate or aspartate (50mgA sertraline) is blended with 20K molecular weight polyethylene oxide(PEO-20K) (350 mg) with other solubilizers and excipients, and the blendis tabletted on a Manesty Type-F3-press. The tablets are spray-coatedwith a solution of cellulose acetate/hydroxypropylcellulose (1:1) in a9:1 acetone/methanol solution, to a final coating weight of 15% of thetotal coated tablet weight.

EXAMPLE 24

This example describes swelling hydrogel controlled release sertralinetablets. Sertraline hydrochloride or acetate or lactate or aspartate (50mgA sertraline) is blended with 100K molecular weight polyethylene oxide(PE-100K) (350 mg) with other solubilizers and excipients, and the blendis tabletted on a Manesty Type-F3-press. The tablets are spray-coatedwish a solution of cellulose acetate in acetone/ethanol, to a final dryweight coating of 14% of the total coated tablet weight A 2 mm diameterhole is drilled (via mechanical, laser or other means) through thecoating on one face of a portion of the tablets. A 2 mm diameter hole isdrilled through the entire center of the tablet for another portion ofthe tablets.

EXAMPLE 25

This example describes swelling hydrogel controlled release sertralinetablets. Sertraline hydrochloride or acetate or lactate or aspartate (50mgA sertraline) is blended with 20K molecular weight polyethylene oxide(PEO-20K) (350 mg) with other solubilizers and excipients, and the blendis tabletted on a Manesty Type-F3-press. The tablets are spray-coatedwith a suspension of sucrose (50/60 mesh) in an acetone solution ofcellulose acetate (2.5%) and PEG-600 (2.5%). The weight ratio ofcellulose acetate to PEG-600 to sucrose in the coating is 1:1:2. Thefinal coating is 15% of the total coating tablet weight.

EXAMPLE 26

This example describes swelling hydrogel controlled release sertralinetablets. Sertraline hydrochloride or acetate or lactate or aspartate (50mgA sertraline) is blended with 20K molecular weight polyethylene oxide(PEO-20K) (350 mg) with other solubilizers and excipients, and the blendis tabletted on a Manesty Type-F3-press. The tablets are spray-coatedwith a 9/1 acetone/methanol solution of cellulose acetate (2.2%) andhydroxypropylcellulose (HPC) (2.2%). The weight ratio of celluloseacetate to HPC in the coating is 1:1, and the final coating is 15% ofthe total coated tablet weight.

EXAMPLE 27

This example describes a perforated coated sustained release sertralinetablet formulation which releases sertraline through a central hole.Sertraline hydrochloride or acetate or lactate or aspartate (50 mgAsertraline) is blended with lactose, magnesium stearate, and optionallyethylcellulose and other excipients, and the blend is tabletted on aManesty Type-F3-press. The tablets are coated with a solution ofethylene vinyl acetate in methanol. After drying, the coating weight is15% of the total weight of the uncoated tablets. A 2 mm diameter hole isdrilled (via mechanical, laser or other means) though the coating on oneface of a portion of the tablets. A 2 mm diameter hole is drilledthrough the entire center of the tablet for another portion of thetablets. The sertraline release rate is varied by varying theethylcellulose content of the tablet.

EXAMPLE 28

This example describes preparation of a pH-triggered (enteric-coated)spatially delayed plus sustained release sertraline tablet. Sertralinesustained release matrix or osmotic or coated hydrogel tablets tabletsare prepared as in Examples 4, 9, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26and 27.

A coating formulation is prepared according to the formulation in Table28-1.

TABLE 28-1 Coating Formulation COMPONENT FUNCTION 6 WT % EudragitL30D-55 enteric polymer 16.0 triethyl citrate plasticizer 1.6 Talcdetackifying agent 4.0 water solvent 78.4

The coating solution is sprayed onto sertraline sustained releasetablets using a Freund HCT-30 Hi-Coated. Coats [Eudragitpolymer+triethyl citrate+talc] are applied ranging from 5-25% of theuncoated tablet weight. These coated tablets release little or nosertraline at the pH of the stomach, and release sertraline in asustained manner (1 mgA/hr to 40 mgA/hr) after moving into the duodenum.

EXAMPLE 29

This example illustrates a process for making pH-triggered spatiallydelayed plus sustained release sertraline multiparticulates.

Sustained release sertraline multiparticulates are prepared as describedin Examples 7 and 8. A Wurster bottom spray fluid bed processor (GlattGPCG-1) is used to apply a delayed release coating. Typical delayedrelease coating levels are ˜5% to ˜50%. The delayed-release coating is asuspension containing 12.3% metacrylic acid copolymers (Eudragit® L 30D-55), 6.2% talc, 1.5% triethyl citrate and 8% water.

Because the delayed release coating is soluble in environments where thepH is greater than 5.5, the multiparticulates thus prepared preventrelease of sertraline from the coated particle cores in the stomach,where the pH is low, and permit release of sertraline from the coatedparticle cores in the small intestine and color, where the pH is greaterthan 5.5.

EXAMPLE 30

This example illustrates a process for making pH-triggeredspatially-delayed plus sustained release sertraline multiparticulates,with a protective layer between the sustained release multiparticualatecore and the pH-triggering delayed release membrane. This dosage formdesign ameliorates any physical or chemical incompatibilities betweenthe sustained release core and the delayed-release membrane. The processcomprises (1) preparing sustained release sertraline multiparticulatecores; (2) applying a protective coat over the core particles; and (3)applying a second, pH-sensitive, delayed release coating over the firstcoat.

Sustained release sertraline multiparticulate cores are prepared asdescribed in Examples 7 and 8. Using a fluid bed processor, onto thesustained release core particles a solution containing 5% plasticiedhydroxypropyl methylcellulose (Opadry®) solution is sprayed until acoating of 10% is applied.

A delayed release coating (typically 5% to 50% of the final weight ofthe coated multiparticulates) is applied using the same fluid bedprocessor as above. The delayed-release coating is a suspensioncontaining 12.3% methacrylic acid copolymers (Eudragit® L 30 D-55), 62%talc, 1.5% triethyl citrate and 80% water.

EXAMPLE 31

This example illustrates the preparation of a pH-triggered spatiallydelayed plus sustained release sertraline coated tablet with a CelluloseAcetate Phthalate Coat.

Sertraline sustained release tablets are manufactured as in Examples 4,9, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26 and 27. The sustained releasetablets are then spray-coated with an acetone solution of celluloseacetate phthalate (CAP) in a HCT-60 Hi-Coater® spray-coating apparatus(Freund Ind. Corp., Tokyo). The CAP is plasticized with 25% (by weight)diethylphtalate (DEP). Sufficient CAP is sprayed onto the tablets toresult in a final coating polymer weight, after drying, of 5-50 wt %,relative to the weight of the uncoated tablet bed.

EXAMPLE 32

This example illustrates the preparation of a pH-triggered spatiallydelayed CAP-coated sustained release sertraline tablet with a barriercoat.

Sustained release sertraline tablets are manufactured as described inExamples 4, 9, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26 and 27. Tabletsare spray coated with a solution of hydroxypropylmethylcellulose (HPMC;Colorcon, Inc.) in water, using a HCT-60 Hi-Coater. In this manner,tablets are coated with a 5 wt % barrier coat of HPMC, relative to theinitial sustained release tablet weight. Tablets are then furtherspray-coated with cellulose acetate phthalate (CAP) and DEP plasticizer(as described in Example 31, in the HCT-60 Hi-Coater. Sufficient CAP issprayed onto the tablets to result in a final coating polymer weight,after drying, of 5-50 wt %, relative to the weight of the uncoatedtablet. The HPMC coat serves as a barrier between the sustained releasesertraline tablet and the pH-sensitive CAP coat. This barrier coatprevents premature dissolution (or weakening) of the CAP coat, e.g., inthe low pH environment of the stomach, potentially caused by a locallyhigher pH in the tablet interior due to the presence of sertraline.

EXAMPLE 33

This example if illustrates the preparation of a pH-triggeredspatially-delay (acrylic resin-coated) plus sustained release sertralinetablet with a barrier coat.

Sustianed release sertraline tablets are manufactured as described inExamples4, 9, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26 and 27. Sustainedrelease sertraline tablets are spray coated with a solution ofhydroxypropylmethylcellulose (HPMC) (Colorcon, Inc.) in water, using aHCT-60 HI-Coater. In this manner, tablets are coated with a 5 wt %barrier coat of HPMC, relative to the initial tablet weight.

A coating formulation is prepared according to the formulation in Table28-1.

The coating solution is sprayed onto HPMC-coated sustained releasesertraline tablets using a Freund HCT-30 Hi-Coater.

The total acrylic resin polymer weight applied is 5-50% of the weight ofthe sertraline sustained release tablet bed. The HPMC undercoat servesas a barrier between sertraline and the pH-sensitive acrylic resin coal.This barrier coat prevents premature dissolution (or weakening) of theacrylic resin coat, e.g., in the low pH environment of the stomach,potentially caused by a locally higher pH in the tablet interior due tothe presence of sertraline.

EXAMPLE 34

This example illustrates preparation of a temporally-delayed(water-activated) plus sustained release sertraline tablet dosage form.

Sustained release sertraline tablets are manufactured as described inExamples 4, 9, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26 and 27. Thesetablets are then coated with a water-soluble and/or water-disintergrabledelay layer, in a tablet coating apparatus such as an HCT-30, HCT-60, orHCT-130 Coater (Freund Inc). The tablet are coated with an aqueoussolution of HPMC to a final coating weight of 5-50% of the final weightof the coated tablet. Heavier coating weights give longer delays beforeinitiation of sertraline release into the use environment (thegastrointestinal lumen). The delay time may also be increased byincorporating small to moderate quantities of poorly water-solublepolymers (including but not limited to ethylcellulose (EC), celluloseacetate (CA), cellulose acetate butyrate) into the coating formulation.For example, the coating formulation may consist of 95:5 HPMC/EC to50:50 HPMC/EC, or 95:5 HPMC/CA to 50:50 HPMC/CA. In the case of suchmixed polymer coating systems, it may be necessary to adjust the solventcomposition to dissolve the mixture of water-soluble and poortywater-soluble polymers. For example, mixtures of acetone ethanol andwater may be used as needed.

In the environment of use, the dosage forms of this example exhibit adelay in sertraline release, during which time the coating polymerdissolves from the sertraline delayed plus sustained release tabletsurface. After the delay, the sertraline sustained release tabletreleases its incorporated sertraline at a rate between 1 mg/hr and 40mg/hr.

EXAMPLE 35

This example illustrates a method for making osmotic tablets comprisinga tablet core containing sertraline-lactate surrounded by asemipermeable asymmetric membrane coating. Tablet cores were made usingequipment standard in the pharmaceutical industry. Tablet corecomponents comprising 13.8 wt % sertraline-lactate, 11 wt % L-asparticacid, 5 wt % calcium acetate 29.5 wt % microcrystalline cellulose, and38.2 wt % fructose were blended, then run through a roller compactor andmilled. This milled material was then blended with 2.5 wt % magnesiumstearate to form the final blended material that was used to maketablets having a total weight of 470 mg on a conventional tablet press(Kilian T-100). Semipermeable asymmetric membrane coatings (as describedin U.S. pat. No. 5,612,059) were applied to the tablets using aside-vented pan coater (LDCS-20, Vector Corp.). The coating solution,comprising 10 wt % cellulose acetate 398-10, 25 wt % polyethylene glycol3350, 15 wt % water, and 72.5 wt % acetone, was spray-coated onto thetablets at a rate of 20 g/min until a 10 wt % coating level on thetablets had been achieved.

EXAMPLE 36

This example illustrates a method for making osmotic tablets comprisinga tablet core containing sertraline-lactate surrounded by asemipermeable asymmetric membrane coating. Tablet cores were made usingequipment standard in the pharmaceutical industry. Tablet corecomponents comprising 13.8 wt % sertraline-lactate, 5 wt % glycerylmonolaurate, 11 wt % L-aspartic acid, 5 wt % calcium acetate, 27 wt %microcrystalline cellulose, and 35.7 wt % fructose were used to make thetablet cores. Initially the glycerol monolaurate was wet granulated with14 wt % microcrystalline cellulose using ethanol (95%) as the wetgranulation solvent. After drying and milling, the wet granulate wasblended with the components listed above (including the balance ofmicrocrystalline cellulose), then run through a roller compactor andmilled. This milled material was then blended with 2.5 wt % magnesiumstearate to form the final blended material that was used to maketablets having a total weight of 470 mg on a conventional tablet press(Kilian T-100). Semipermeable asymmetric membrane coatings (as describedin U.S. Pat. No. 5,612,059) were applied to the tablets using aside-vented pan coater (LDCS-20, Vector Corp.). The coating solution,comprising 10 wt % cellulose acetate 398-10, 2.5 wt % polyethyleneglycol 3350, 15wt % water, and 72.5 wt % acetone; was spray-coated ontothe tablets at a rate of 20 g/min. One batch of tablets was made with a10 wt % coating and a second batch of tablets was made having a 20 wt %coating.

EXAMPLE 37

Sertraline acetate. Sertraline base (the compound of Preparation AA,200.2 mg) was dissolved in ethyl acetate (200 μL) in a 5 ml reactionvial. Glacial acetic acid (41.2 μL) was added to the sertraline basesolution with stirring. An additional 500 μL of ethyl acetate was addedto facilitate stirring. The reaction mixture was allowed to granulate atroom temperature for five hours. The solids were filtered, washed with10 mL of ethyl acetate and then dried in a vacuum oven at 40° C. for 20hour. The yield was determined to be 16%. mp 126° C.

EXAMPLE 38

Sertraline acetate. Sertraline base, (the compound of Preparation AA,200 mg) was dissolved in hexane (1.5 mL) in a 10 mL reaction vial. Thesolution was heated to 40° C. Glacial acetic acid (41.2 μL) was added tothe sertraline base solution. The reaction mixture was allowed to coolto room temperature and then granulate for one hour. The solids werefiltered and dried in a vacuum oven at 40° C. for 72 hours. The yieldwas determined to be 90%. mp 126° C.

EXAMPLE 39

Sertraline acetate. Sertraline hydrochloride (125 g) was slurried in amixture of water (1 L) and (2.5 L). NaOH (25% aqueous, 35 mL) was added.Sertraline base partitioned into the hexane phase. The hexane layer wasseparated. The aqueous layer was extracted a second time with hexane(500 mL). The hexane layers were combined. The solution of sertralinebase in hexane was heated to 50° C. Glacial acetic acid (23 ml) wasadded to the solution of sertraline base. The reaction mixture wasstirred at 50° C. for 30minutes. The reaction mixture was allowed tocool to room temperature and stirred at room temperature overnight. Thecrystals were filtered and washed five times with a total of 250 mL ofhexane. The solids were dried at 40° C. in a vacuum oven for 48 hours.The yield was 89%. mp 126° C.

EXAMPLE 40

Single Crystal X-ray Analysis. A representative was surveyed and a 1 Ådata set (maximum sin θ/λ0.5) was collected on a Siemens R3RA/vdiffractometer, Siemens Analytical X-ray Systems, Inc., 6300 EnterpriseLane, Madison, Wis. 53719-1173. Atomic scattering factors were takenfrom the International Tables for X-ray Crystallography. InternationalTables for X-ray Crystallography, Vol. IV, pp. 55, 99, 149 Birmingham:Kynoch Press, 1974. All crystallographic calculations were facilitatedby the SHELXTL system. G. M. Sheldrick SHELXTL User Manual, NicoletInstrument Corp., 5225 Verona Rd, Madison, Wis. 53711, 1981). Alldiffractometer data were collected at room temperature. Pertinentcrystal, data collection, and refinement parameters are summarized inTable 40-1 below.

A trial structure was obtained by direct methods. This trial structurerefined routinely. A difference map revealed a small amount of waterlocated on a two-fold axis. Refinement indicated that the population ofthis water was 0.25. Hydrogen positions were calculated whereverpossible. The methyl hydrogens and the hydrogens on nitrogen werelocated by difference Fourier techniques. The hydrogens on the waterwere not located. The hydrogen parameters were added to the structurefactor calculations but were not refined. The shifts calculated in thefinal cycle of least squares refinement were all less than 0.1 of theircorresponding standard deviations. The final R-index was 8.97%. A finaldifference Fourier revealed no missing or misplaced electron density.

The refined structure, shown in FIG. 1, was plotted using the SHELXTLplotting package described in said SHELXTL User Manual. The absoluteconfiguration was not established.

TABLE 40-1 Crystal Parameters of Sertraline-Acetate Formula C₁₇H₁₈NCl₂⁺C₂H₃O₂ ⁻−0.25 H₂O (371.3) Crystallization Medium water Crystal size(mm) 0.10 × 0.16 × 0.22 Cell dimensions a = 15.629(8) Å b = 8.695(3) Å c= 15.048(3) Å α = 90.0° β = 110.45(3)° γ = 90.0° V = 1916(1) Å SpaceGroup C2 Molecules/unit cell 4 Density, calculated, g/cm³ 1.287 LinearAbsorption Factor, 3.144 mm⁻¹

TABLE 40-2 Atomic Coordinates (× 10⁴) and equivalent isotropicdisplacement coefficients (Å² × 10³) x y z U (eq)* C(1) 8321 (14) 10711(22)  −3626 (12) 79 (2) C(2) 7559 (13) 10583 (20)  −3227 (12) 66 (2)C(3) 7581 (14) 8997      −2770 (12) 83 (2) C(4) 8453 (11) 8847 (21)−1902 (11) 67 (2) C(5) 9260 (11) 9344 (22) −2182 (12) 66 (2) C(6) 9268(14) 10390 (22)  −2917 (12) 87 (2) C(7) 10033 (16)  10928 (24)  −3028(14) 103 (2)  C(8) 10898 (14)  10516 (24)  −2347 (14) 91 (2) C(9) 10883(16)  9557 (24) −1637 (14) 97 (2) C(10) 10115 (12)  9074 (21) −1513 (12)67 (2) C(11) 8555 (14) 7256 (22) −1473 (14) 79 (2) C(12) 8418 (12) 6975(22)  −625 (12) 66 (2) C(13) 8514 (14) 5542 (25)  −215 (12) 89 (2) C(14)8760 (12) 4314 (21)  −708 (18) 90 (2) C(15) 8861 (18) 4526 (27) −1587(15) 132 (2)  C(16) 8763 (14) 6002 (22) −1905 (13) 88 (2) N(17) 8112(9)  9728 (19) −4522 (10) 65 (2) C(18) 8616 (14) 10130 (25)  −5161 (13)98 (2) C1(19) 8377 (5)  5313 (12)   862 (4) 127 (2)  C1(20) 8816 (6) 2473 (13) −178 (6) 144 (2)  C(1A) 9993 (16) 5929 (28) −3685 (16) 157(3)  C(2A) 9026 (12) 5594 (27) −4223 (12) 83 (2) O(3A) 8771 (11) 4331(19) −4476 (12) 119 (2)  O(4A) 8464 (12) 6651 (19) −4306 (11) 116 (2) O(1W) 10000 (37)  2700 (33) −5000 (37) 132 (4)  *Equivalent isotropic Udefined as one third of the trace of the orthogonalized U_(ij) tensor.

EXAMPLE 41

Osmotic Tablets of Sertraline Acetate. This example illustrates a methodfor making osmotic tablets comprising a tablet core containingsertraline acetate surrounded by a semipermeable asymmetric membranecoating. Tablet cores were made using equipment standard in thepharmaceutical industry. Tablet core components comprising sertralineacetate (14 wt %), ascorbic acid (50 wt %), lactose (20 wt %),microcrystalline cellulose (15 wt %) and polyethylene glycol stearylether (1 wt %, Myrj 52, Sigma Chemical, St. Louis, Mo.) were blended byhand using a mortar and pestle. The blended material was used to maketablets having a total weight of 470 mg on a single-station tablet press(F-press). Semipermeable asymmetric membrane coatings (as described inU.S. Pat. No. 5,612,069, the teachings of which are incorporated hereinby reference) were applied to the tablets using a side-vented pan coater(LDCS-20, Vector Corp., 675 44th St, Marion, Iowa 52302). The coatingsolution, comprising ethyl cellulose S-100 (6 wt %), polyethylene glycol3350 (4 wt %), water (10 wt %), and acetone (80 wt %), was spray-coatedonto the tablets at a rate of 20 g/minute until a 10 wt % coating levelon the tablets had been achieved.

EXAMPLE 42

This example illustrates a process for making multiparticulates for usein making delayed-release dosage forms designed to release sertralinepredominantly below the stomach. The process comprises (1) preparinguncoated sertraline acetate multiparticulate cores; (2) applying aprotective coat over the core particles; and (3) applying a second,pH-sensitive, delayed release coating over the first coat.

Multiparticulate cores containing drug are prepared using a fluid bedprocessor with rotor insert (Model GPCG-1, Glatt Air Techniques, Ramsey,N.J. 07446). The rotor bowl is initially charged with 400 gA ofsertraline drug (as sertraline acetate, sertraline lactate or sertralineaspartate) and a binder solution containing 5% poly(ethyl acrylate,methyl acrylate)(Eudragit® NE-30-D), 5% plasticized hydroxypropylmethylcellulose (Opadry®, Colorcon, West Point, Pa. 19486) and 90% wateris sprayed into the rotating bed until an average core granule size ofabout 250 μm is achieved.

Onto the uncoated core particles in the same fluid bed processor withrotor insert, a binder solution containing 5% plasticized hydroxypropylmethylcellulose (Opadry®) solution is sprayed until a coating of 10% isapplied. This intermediate coating enhances the adhesion to the coreparticles of the final delayed release coating.

A delayed release coating (typically 5% to 50% is required to meet thedelayed release criterion) is applied using the same fluid bed processoras above. The delayed-release coating is a suspension containing 12.3%methacrylic acid copolymers (Eudragit® L 30 D-55, Rohm GMBH, Darmstadt,Germany; U.S. Office: Somerset, N.J.) 6.2% talc, 1.5% triethyl citrateand 80% water. The final product is a delayed-release multiparticulatewith particles having an average size of about 300 μm.

EXAMPLE 43

Sertraline L-lactate. Sertraline base (the compound of Preparation AA,200 mg) was dissolved in ethyl acetate (200 μL) in a 10 mL conicalreaction vial. L-Lactic acid (solid, 68.5 mg) was separately dissolvedin ethyl acetate(100 μL). The L-lactic acid solution was added to thesertraline base solution under constant stirring with a magneticstirrer. A precipitate was observed within about 2 minutes aftercomplete addition of the L-lactic acid solution to the sertraline basesolution. The reaction mixture was allowed to granulate overnight (18hour) at room temperature. The precipitate was filtered and the solidwas rinsed with 1 mL of ethyl acetate. The solid was dried in a vacuumoven at 40° C. for 20 hours. The dried sold was characterized andidentified as the L-lactate salt of sertraline. The yield was determinedto be 72%. mp 153° C.

EXAMPLE 44

Sertraline L-lactate. Sertraline base (the compound of Preparation AA,1.0 g) was dissolved in ethyl acetate (20 mL) in a 50 mL round bottomflask and the solution was heated to 40° C. L-Lactic acid (342.5 mg) wasseparately dissolved in ethyl acetate (5 mL). The L-latic acid solutionwas added in small portions to the solution in the round bottom flaskwhich was constantly stirred with a magnetic stirred. The reactionmixture was stirred at 40° C. for 2 hours after the addition of theL-lactic acid solution was complete. The reaction mixture was thenallowed to cool to room temperature and the solids were filtered. Thesolids were washed with 5 mL of ethyl acetate and then dried undervacuum at 40° C. for 24 hours. The dried solid was identified as theL-lactate salt of sertraline. The yield was calculated to be 86%. mp153° C.

EXAMPLE 45

Sertraline L-lactate. Sertraline base (10 g)was dissolved in isopropanol(150 mL) in a 500 mL round bottom flask and the solution was heated to40° C. L-Lactic acid (3.4 g) was separately dissolved in ethyl acetate(25 mL). The L-lactic acid solution was added in small portions to thesolution in the round bottom flask which was constantly stirred with amagnetic stirrer. The reaction mixture was stirred at 40° C. for 4 hoursafter the addition of the L-lactic acid solution was complete. Thereaction mixture was then allowed to cool to room temperature and thesolids were filtered. The solids were washed with 50 mL of hexane andthen dried under vacuum at 40° C. for 48 hours. The dried solid wasidentified as the L-lactate salt of sertraline. The yield was calculatedto be 94%. mp 153° C.

EXAMPLE 46

Sertraline L-lactate. Sertraline mandelate (750 grams) was slurried in amixture of water (3.9 L) and ethyl acetate (3.9 L). The slurry wascooled to 15° C. NaOH (25% aqueous, 250 mL) was added, resulting in asolution with pH 9.6. The free base of sertraline was partitioned intothe ethyl acetate layer which was separated. The aqueous layer wasextracted with an additional 3.4 liters of ethyl acetate. The combinedethyl acetate layers were washed with 3.9 liters of water. The ethylacetate layer containing sertraline base was concentrated under vacuumand filtered to clarify the solution. To this solution was addedL-lactic acid (155 g). The reaction mixture was granulated hr 20 hoursat room temperature. The solids were filtered, washed 4 times with ethylacetate(400 mL each time). The crystals were dried overnight undervacuum at 40° C. The yield was calculated to be 84%. mp 153° C.

EXAMPLE 47

Sertraline L-lactate. Sertraline hydrochloride (300 g) was slurried in a3:1 mixture of water (3 liters) and ethyl acetate (1 liter). The pH ofthe slurry was adjusted to 8.0 by the addition approximately 1 liter of1N sodium hydroxide solution. The free base of sertraline partitionedinto the ethyl acetate phase. The two phases were allowed to separatecompletely by allowing the biphasic solution to stand overnight withoutagitation. The ethyl acetate layer was then separated and washed twicewith 3 liters of deionized water to remove chloride ions. The finalethyl acetate layer containing sertraline base was concentrated to 300mL under vacuum to remove residual water. The ethyl acetate solutioncontaining sertraline base was heated to 40° C. L-lactic acid wasdissolved in ethyl acetate to form a 7.5 M solution. The lactic acidsolution was added to the sertraline base solution in small portionswith constant agitation. The mixture was allowed to stir and granulateovernight (16-20 hours). The crystals were filtered and washed 4 timeswith an equal volume (200 mL each) of ethyl acetate. The crystals weredried overnight in a vacuum oven at 40° C. The yield was 97%. mp 153° C.

EXAMPLE 48

Single Crystal X-Ray Analysis. A representative crystal was surveyed anda 1 Å data set (maximum sin θ/λ=0.5) was collected on a Siemens R3RA/vdiffractometer. Atomic scattering factors were taken from theInternational Tables for X-ray Crystallography, Vol. IV, Kynoch Press,Birmingham, 1974, pp. 55, 99 and 149. All crystallographic calculationswere facilitated by the SHELTXL (see G. M. Sheldrick, SHELTXL. UserManual, Nicolet Instrument Corp., 5225 Verona Rd, Madison, Wis. 53711,1981) system. All diffractometer data were collected at roomtemperature. Pertinent crystal, data collection, and refinementparameters are summarized in Table 48-1.

TABLE 48-1 Crystal Parameters of Sertraline L-lactate Formula C₁₇H₁₈NCl₂⁺C₃H₅O₃ ⁻ (396.3) Crystallization Medium ethyl acetate Crystal size (mm)0.07 × 0.07 × 0.11 Cell dimensions a = 8.660(5) Å b = 24.43(1) Å c =9.382(3) Å α = 90.0° β = 91.94(3)° γ = 90.0° V = 1984(2) Å³ Space GroupP2₁ Molecules/unit cell 4 Density, calculated, g/cm³ 1.327 LinearAbsorption Factor, mm⁻¹ 3.101

A trial structure was obtained by direct methods. This trial structurerefined routinely. Hydrogen positions were calculated wherever possible.The methyl hydrogens and the hydrogens on nitrogen and oxygen werelocated by difference Fourier techniques. The hydrogen parameters wereadded to the structure factor calculations but were not refined. Theshifts calculated in the final cycle of least squares refinement wereall less than 0.1 of their corresponding standard deviations. The finalR-index was 5.49%. A final difference Fourier revealed no missing ormisplaced electron density.

The refined structure, shown as FIG. 3, was plotted using the SHELTXLplotting package. The absolute configuration was determined by themethod of Ibers and Hamilton (Hamilton, Acta Cryst, 1965, 18, 502-510and Ibers et al., Acta Cryst., 1964, 17, 781-782). The X-Ray absoluteconfiguration was in agreement with the L-laclate configuration. Theatomic coordinates are set forth in Table 48-2.

TABLE 48-2 Atomic Coordinates (× 10⁴) and equivalent isotropicdisplacement coefficients (Å² × 10³) x y z U (eq)* C(1) −4173(13)4373(5) 7866(10) 44(2) N(1A) −4127(10) 3773(4) 7483(9)  47(2) C(1B)−5542(14) 3455(6) 7614(12) 69(2) C(2) −2556(12) 4576(6) 8220(10) 54(2)C(3) −1658(12) 4605(5) 6877(11) 55(2) C(4) −2328(12) 5027(5) 5834(10)44(2) C(4A) −4064(12) 4979(5) 5658(10) 45(2) C(5) −4860(13) 5273(5)4565(11) 49(2) C(6) −6411(15) 5250(6) 4430(12) 68(2) C(7) −7291(13)4981(6) 5430(13) 68(2) C(8) −6563(13) 4705(5) 6491(12) 56(2) C(8A)−4955(12) 4700(5) 6662(10) 39(2) C(1′) −1539(12) 5015(5) 4411(10) 46(2)C(2′) −1022(12) 5517(5) 3816(12) 52(2) C(3′)  −308(13) 5493(5) 2508(11)52(2) C1(1)   243(5) 6117(2) 1757(4)  91(1) C(4′)   −9(13) 5024(6)1820(11) 54(2) C1(2)   972(4) 4996    258(3) 81(1) C(5′)  −486(14)4545(5) 2414(11) 56(2) C(6′) −1219(14) 4538(5) 3694(11) 52(2) C(1X)   495(13) 7219(5) −5303(11)   47(2) N(1XA)    648(11) 7826(4)−4926(9)    50(2) C(1XB)  −814(13) 8109(5) −4598(12)   58(2) C(2X)  2126(14) 7016(5) −5601(12)   67(2) C(3X)   3130(13) 6938(6)−4263(11)   64(2) C(4X)   2437(13) 6525(5) −3240(10)   53(2) C(4XA)   702(12) 6586(5) −3183(11)   46(2) C(5X)  −45(14) 6304(5) −2112(12)  55(2) C(6X) −1610(15) 6299(5) −1995(13)   65(2) C(7X) −2501(16) 6604(6)−2945(14)   80(2) C(8X) −1807(13) 6890(5) −4024(12)   56(2) C(8XA) −206(12) 6900(5) −4117(10) 39(2) C(1X′)   3233(13) 6545(5) −1796(10)49(2) C(2X′)   3944(14) 6083(5) −1250(11) 58(2) C(3X′)   4642(13)6084(5)  101(11) 52(2) C1(3)   5554(5)  5501(2) 743(3) 85(1) C(4X′)  4732(14) 6569(6)  875(11) 62(2) C1(4)   5695(4)  6600(2) 2528(3) 78(1) C(5X′)   3978(14) 7023(5)  350(11) 62(2) C(6X′)   3293(15) 7006(5) −982(11)   63(2) C(1Y)   1318(16) 2575(6) 9581(14) 106(2)  C(2Y)   540(13) 3113(5) 9839(11) 57(2) O(3Y)    103(10) 3150(5) 11268(8) 87(2) C(4Y)  −786(14) 3217(5) 8778(12) 49(2) O(5Y)  −479(11) 3255(4)7509(8)  86(2) O(6Y) −2081(10) 3239(4) 9294(8)  65(2) C(1Z)   6352(15)8746(8) −2633(15)   110(2)  C(2Z)   4677(13) 8843(6) −2407(12)   66(2)O(3Z)   4349(11) 8757(5) −1000(8)    101(2)  C(4Z)   3602(14) 8483(5)−3343(11)   50(2) O(5Z)   3800(10) 8497(4) −4676(7)    66(2) O(6Z)  2594(10) 8209(4) −2782(7)    60(2) *Equivalent isotropic U is definedas one third of the trace of the orthogonalized U_(ij) tensor.

EXAMPLE 49

Osmotic Tablets of Sertraline L-Lactate. This example illustrates amethod for making osmotic tablets comprising a tablet core containingsertraline L-lactate surrounded by a semipermeable asymmetric membranecoating. Tablet cores were made using equipment standard in thepharmaceutical industry. Tablet core components comprising sertralineL-lactate (13.8 wt %), L-aspartic acid (11 wt %), calcium acetate (5 wt%), microcrystalline cellulose (29.5 wt %), and fructose (38.2 wt %)were blended, then run through a roller compactor and milled. Thismilled material was then blended wish 2.5 wt % magnesium stearate toform the final blended material that was used to make tablets having atotal weight of 470 mg on a conventional tablet press (Kilian T-100).Semipermeable asymmetric membrane coatings (as described in U.S. Pat.No. 5,612,059, the teachings of which are incorporated herein byreference) were applied to the tablets using a side-vented pan coater(LDCS-20, Vector Corp., 675 44th St, Marion, Iowa 52302). The coatingsolution, comprising 10 wt % cellulose acetate 398-10, 2.5 wt %polyethylene glycol 3350, 15 wt % water, and 72.5 wt % acetone, wasspray-coated onto the tablets at a rate of 20 g/minute until a 10 wt %coating level on the tablets had been achieved.

EXAMPLE 50

Osmotic Tablets of Sertraline L-Lactate. This example illustrates amethod for making osmotic tablets comprising a tablet core containingsertraline L-lactate surrounded by a semipermeable asymmetric membranecoating. Tablet cores were made using equipment standard in thepharmaceutical industry. The tablet cores were prepared as follows:Glycerol monolaurate (5 wt %) was wet granulated with microcrystallinecellulose (14 wt %) using ethanol (95%) as the wet granulation solvent.After drying and milling, the wet granulate was blended with sertralineL-lactate (13.8 wt %), L-aspartic acid (11 wt %), calcium acetate (5 wt%), microcrystalline cellulose (an additional 13 wt %), and fructose(35.7 wt %). After all of the components were added, the granulate wasrun through a roller compactor and milled. The milled material wasblended with magnesium stearate (2.5 wt %) to form the final blendedmaterial that was used to make tablets having a total weight of 470 mgon a conventional tablet press (Killan T-100, Kilian & Co., 415 SargonWay Unit 1, Horsham, Pa. 19044). Semipermeable asymmetric membranecoatings (as described in U.S. Pat. No. 5,612,059) were applied to thetables using a side-vented pan coater LDCS-20, Vector Corp.). Thecoating solution, comprising 10 wt % cellulose acetate 395-10, 2.5 wt %polyethylene glycol 3350, 15 wt % water, and 72.5 wt % acetone, wasspray-coated onto the tablets at a rate of 20 g/minute. One batch oftablets was made with a 10 wt % coating and a second batch of tabletswas made having a 20 wt % coating.

EXAMPLE 51

Encapsulated Solution Dosage Form of Sertraline L-Lactate. Solutions ofsertraline L-lactate are prepared in Capmul MCM™ (mono- anddi-glycerides of caprylic and capric acids, Abitec Corporation,Columbus, Ohio 43219) at a concentration of 75 mgA/mL. The solutions areencapsulated in soft gelatin at a fill volume of 0.67 mL, yielding aunit dose of 50 mgA.

EXAMPLE 52

Sertraline L-aspartate. Sertraline free base (the compound ofPreparation AA, 200.3 mg) was dissolved in ethyl acetate (800 μL, whichhad previous been saturated with water). L-aspartic acid (95.53 mg) wassuspended in ethyl acetate (3 mL, which had previously been saturatedwith water). The aspartic acid suspension was added to the sertralinefree base solution. The reaction mixture was stirred for 24 hours. Thesolids were filtered, washed with ethyl acetate saturated with water andthen dried at 40° C. in a vacuum oven for 48 hours. The yield ofsertraline L-aspartate was 96.4%. mp 247° C.

Preparation AA

Sertraline free base. Sertraline hydrochloride (5 grams) was dissolvedin water (one liter). To this solution the required amount of 1N NaOHwas added until the pH of the solution was adjusted to 8.0. Theresulting solids were filtered and washed with deionized water (50 mLper gram of solid). The solids were dried at 40° C. in a vacuum oven for48 hours. The yield was 98%. mp 67° C.

Preparation BB

Sertraline free base. Sertraline hydrochloride (300 g) was slurried in a3.1 mixture of water (3 liters) and ethyl acetate (1 liter). The pH ofthe slurry was adjusted to 8.0 by the addition of approximately 1 literof 1N sodium hydroxide solution. The free base of sertraline partitionedinto the ethyl acetate phase. The two phases were allowed to separatecompletely by allowing the biphasic solution to stand overnight withoutagitation. The ethyl acetate layer was then separated and washed twicewith 3 liters of deionized water to remove chloride ions. The finalethyl acetate layer containing sertraline base was concentrated to 300mL under vacuum to remove residual water.

What is claimed is:
 1. A sustained-release dosage form suitable for oraladministration to a mammal, comprising sertraline, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,which dosage form releases sertraline into a use environment at a ratenot exceeding 0.8 mgA/hr/kg, provided said dosage form (1) releases notmore than 70% of the sertraline contained therein within the first hourfollowing entry into said use environment and (2) releases sertraline ata rate of at least 0.02 mgA/hr/kg.
 2. A dosage form as defined in claim1, wherein said sertraline is present as sertraline free base,sertraline hydrochloride, sertraline aspartate, sertraline acetate orsertraline lactate.
 3. A dosage form as defined in claim 1, wherein saidmammal is a human.
 4. A dosage form as defined in claim 1, in the formof a matrix tablet which remains substantially intact during the periodof sustained release.
 5. A dosage form as defined in claim 1, in theform of a disintegrating martix tablet.
 6. A dosage form as defined inclaim 1, in the form of a matrix tablet partially coated with a polymerwhich impedes the release of sertraline.
 7. A dosage form as defined inclaim 1, in the form of an osmotic tablet.
 8. A dosage form as definedin claim 1, in the form of a membrane-coated hydrogel tablet.
 9. Adosage form as defined in claim 1, which is multiparticulate.
 10. Adosage form as defined in claim 1, in the from of a membrane-coateddiffusion-based, capsule, tablet or multiparticulate.
 11. Asustained-release dosage form suitable for administration to a mammal,comprising sertraline, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier, which dosage form releasessertraline into a use environment at a rate not exceeding 40 mgA/hr,provided said dosage form (1) releases not more than 70% of thesertraline contained therein within the first hour following entry intosaid use environment and (2) releases sertraline at a rate of at least 1mgA/hr.
 12. A dosage form as defined in claim 11 wherein said sertralineis present as sertraline free base, sertraline hydrochloride, sertralineaspartate, sertraline acetate or sertraline lactate.
 13. A dosage formas defined in claim 11, wherein said mammal is a human.
 14. A dosageform as defined in claim 11, in the form of a matrix tablet whichremains substantially intact during the period of sustained release. 15.A dosage form as defined in claim 11, in the form of a disintegratingmatrix tablet.
 16. A dosage form as defined in claim 11, in the form ofa matrix tablet partially coated with a polymer which impedes therelease of sertraline.
 17. A dosage form as defined in claim 11, in theform of an osmotic tablet.
 18. A dosage form as defined in claim 11, inthe form of a membrane-coated hydrogel tablet.
 19. A dosage form asdefined in claim 11, which multiparticulate.
 20. A dosage form asdefined in claim 11, in the form of a membrane-coated fiffusion-basedtablet or multiparticulate.
 21. A sustained release dosage form suitablefor oral administration to a mammal, comprising sertraline or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier, which dosage form releases sertraline at a rate lessthan 40 mgA/hr in vitro when dissolution tested in a USP-2 apparatuscontaining 900 ml of acetate buffer, pH 4.0, which is 0.075 M in NaCl asfollows: (1) if said dosage form is a sustained release tablet or anon-disintegrating sustained release capsule, said USP-2 apparatus isequipped with a paddle stirring at 50 rpm; (2) if said dosage form is amultiparticulate, said USP-2 apparatus is equipped with a paddlestirring at 100 rpm; provided said dosage form (a) releases not morethan 70% of the sertraline contained therein within the first hourfollowing initiation of testing and (b) releases sertraline at a rate ofat least 1 mgA/hr.
 22. A dosage form as defined in claim 21, whereinsaid sertraline is present as sertraline free base, sertralinehydrochloride, sertraline aspartate, sertraline acetate or sertralinelactate.
 23. A dosage form as defined in claim 21, wherein said mammalis a human.
 24. A dosage form as defined in claim 21, in the form of amatrix tablet which remains substantially intact during the period ofsustained release.
 25. A dosage form as defined in claim 21, in the formof a disintegrating matrix tablet.
 26. A dosage form as defined in claim21, in the form of a matrix tablet partially coated with a polymer whichimpedes the release of sertraline.
 27. A dosage form as defined in claim21, in the form of an osmotic tablet.
 28. A dosage form as defined inclaim 21, in the form of a membrane-coated hydrogel tablet.
 29. A dosageform as defined in claim 21, which is multiparticulate.
 30. A dosageform as defined in claim 21, in the form of a membrane-coateddiffusion-based tablet or multiparticulate.
 31. A temporally delayedplus sustained release dosage form suitable for oral administration to amammal, comprising sertraline or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier, which dosage form,following ingestion by said mammal, releases sertraline into saidmammal's GI tract at a rate less than 1 mgA/hr for an initial delayperiod of up to 3 hours, and which thereafter release sertraline at arate of from 1 mgA/hr to 40 mgA/hr, provided said dosage form releasesnot more tan 70% of the sertraline contained therein within the firsthour after said delay period.
 32. A dosage form as defined in claim 31,wherein said delay period is up to two hours.
 33. A dosage form asdefined in claim 31, wherein the rate of release following said delayperiod is from 1 mgA/hr to 30 mgA/hr.
 34. A dosage form as defined inclaim 31, wherein said sertraline is present as sertraline free base,sertraline hydrochloride, sertraline aspartate, sertraline acetate orsertraline lactate.
 35. A dosage form as defined in claim 31, whereinsaid mammal is a human.
 36. A temporally delayed plus sustained releasedosage form suitable for administration to a mammal, said dosage formhaving an initial temporal delay period of up to 3 hours, comprisingsertraline or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier, which dosage form, when dissolutiontested in vitro in a USP-2 apparatus containing 900 ml of acetatebuffer, pH 4.0, which is 0.075 M in NaCl, releases sertraline at a rateless than 1 mgA/hr for a period corresponding to said delay period and,thereafter, releases sertraline at a rate of from 1 mgA/hr to 40 mgA/hr,provided the dosage form releases not more than 70% of the remainingsertraline contained therein within the first hour following said delay.37. A dosage form as defined in claim 36, wherein said delay period isup to two hours.
 38. A dosage form as defined in claim 36, wherein therate of release following said delay period is from 1 mgA/hr to 30mgA/hr.
 39. A dosage form as defined in claim 36, wherein saidsertraline is present as sertraline free base, sertraline hydrochloride,sertraline aspartate, sertraline acetate or sertraline lactate.
 40. Adosage form as defined in claim 36, wherein said mammal is a human. 41.A dosage form as defined in claim 36, in he form of a tablet.
 42. Adosage form as defined in claim 36, which is multiparticulate.
 43. Aspatially delayed plus sustained release dosage form suitable for oraladministration to a mammal, comprising sertraline or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier, whichdosage form, following ingestion by said mammal, releases sertralineinto said mammal's stomach at a rate less than 1 mgA/hr, and which,after having passed into said mammal's small intestine, effectssustained release at a rate of from 1 mgA/hr to 40 mgA/hr, provided saiddosage form releases not more than 70% of the sertraline containedtherein with the first hour after passing into said mammal's smallintestine.
 44. A dosage form as defined in claim 43, wherein the onsetof sustained release is pH-triggered.
 45. A dosage form as defined inclaim 44, comprising a sustained release dosage form coated with apolymer that prevents release of sertraline at the pH of the stomach,but which is permeable to sertraline at the pH of the small intestine.46. A dosage form as defined in claim 44, wherein said sustained releasedosage form is multiparticulate.
 47. A dosage form as defined in claim44 wherein said sustained release dosage form is a tablet.
 48. A dosageform as defined in claim 43, which is enzyme-triggered.
 49. A dosageform as defined in claim 48, comprising a sustained release dosage formcoated with a membrane having a hydrophobic liquid entrained within thepores thereof, said hydrophobic liquid being substantially impermeableto water and sertraline, but capable of changing, through enzymaticdegradation, so that said membrane becomes substantially permeable towater and sertraline when said dosage form moves into the environment ofthe small intestinal lumen.
 50. A dosage form as defined in claim 48,wherein said sustained release dosage form is mutliparticulate.
 51. Adosage form as defined in claim 48, wherein said sustained releasedosage form is a matrix.
 52. A dosage form as defined in claim 43,wherein said sertraline is present as sertraline free base, sertralinehydrochloride, sertraline aspartate, sertraline acetate or sertralinelactate.
 53. A dosage form as defined in claim 43, wherein said mammalis a human.
 54. A sustained release pH-triggered dosage form suitablefor oral administration to a mammal, said dosage form having an initialdelay period prior to the onset of sustained release, comprisingsertraline or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier, which dosage form, when tested invitro in a USP-2 apparatus, releases sertraline into 0.1 N HCl at a rateless than 1 mgA/hr for 1 hour and, thereafter, releases sertraline intophosphate buffer, pH 6.8 containing 1% polysorbate 80 at a me of from 1mgA/hr to 40 mgA/hr, provided the dosage form releases not more than 70%of the remaining sertraline contained therein within the first hourfollowing said delay.
 55. A dosage form as defined in claim 54,comprising a sustained release dosage form coated with a coatingcomprising a polymer that prevents release of sertraline in said HCl ata rate exceeding 1 mgA/hr, but which is permeable to and allowssustained release of sertraline in said phosphate buffer.
 56. A dosageform as defined in claim 55, wherein said sustained release dosage formis multiparticulate.
 57. A dosage form as defined in claim 55, whereinsaid sustained release dosage form is a tablet.
 58. A dosage form asdefined in claim 54, wherein said sertraline is present as sertralinefree base, sertraline hydrochloride, sertraline aspartate, sertralineacetate or sertraline lactate.
 59. A dosage form as defined in claim 54,wherein said mammal is a human.
 60. A sustained release enzyme-triggereddosage form suitable for oral administration to a mammal, said dosageform having an initial delay period prior to the onset of sustainedrelease, comprising sertraline or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier, which dosage form,when tested in vitro in a USP apparatus releases sertraline into 0.1 NHCl at a rate less than 1 mgA/hr for a period of 1 hour and, thereafter,releases sertraline at a rate of from 1 mgA/hr to 40 mgA/hr intophosphate buffer, pH 6.8, containing 1% polysorbate 80 and in thepresence of an enzyme suitable for triggering the onset of saidsustained release, provided the dosage form releases not more than 70%of the remaining sertraline contained therein within the first hourfollowing said delay.
 61. A dosage form as defined in claim 60,comprising a sustained release dosage form coated with a membrane havinga hydrophobic liquid entrained within the pores thereof, saidhydrophobic liquid being substantially impermeable to water andsertraline in said acid, but capable of changing in said buffer, thoughenzymatic degradation in the presence of said enzyme, so that saidmembrane becomes substantially permeable to water and sertraline.
 62. Adosage form as defined in claim 60, wherein said sustained releasedosage form is multiparticulate.
 63. A dosage form as defined in claim60, wherein said sustained release dosage form is a tablet.
 64. A dosageform as defined in claim 60, wherein said sertraline is present assertraline free base, sertraline hydrochloride, sertraline aspartate,sertraline acetate or sertraline lactate.
 65. A dosage form as definedin claim 60, wherein said mammal is a human.
 66. A sustained releasedosage form suitable for oral administration to a mammal, comprisingsertraline, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, which dosage form, when orallydosed to said mammal, results in a maximum sertraline plasmaconcentration, C_(max), which is less than 80% of the C_(max) determinedween an equal dose of sertraline is orally administered in the form ofan immediate release bolus provided said sustained release dosage form(1) releases not more than 70% of the sertraline contained thereinwithin the first hour following ingestion and (2) releases sertraline ata rate of at least 1 mgA/hr.
 67. A dosage form as defined in claim 66,which provides a total blood drug exposure that is not proportionatelydecreased as much as C_(max).
 68. A dosage form as defined claim 66,wherein said sertraline is present as sertraline free base, sertralinehydrochloride, sertraline aspartate, sertraline acetate or sertralinelactate.
 69. A dosage form as defined in claim 66, wherein said mammalis a human.
 70. A dosage form as defined in claim 66, in the form of atablet.
 71. A dosage form as defined in claim 66, which ismultiparticulate.
 72. A dosage form as defined in claim 66, which is adelayed plus sustained release form exhibiting a delay period of up tothree hours prior to the onset of sustained release, said dosage formreleasing sertraline at a rate of not more than 1 mgA/hr during saiddelay period.
 73. A dosage form as defined in claim 72, wherein saiddelay is temporal.
 74. A dosage form as defined in claim 72, whereinsaid delay is spatial.
 75. A method for treating a psychiatric illness,premature ejaculation, chemical dependency, premenstrual dysphoricdisorder, or obesity, comprising administering to a mammal in need ofsuch treatment, a therapeutically effective amount of sertraline in asustained-release oral dosage form as defined in claim
 1. 76. A methodfor treating a psychiatric illness, premature ejaculation, chemicaldependency, premenstrual dysphoric disorder, or obesity, comprisingadministering to a mammal in need of such treatment, a therapeuticallyeffective amount of sertraline in a sustained-release oral dosage formas defined in claim
 1. 77. A method for treating a psychiatric illness,premature ejaculation, chemical dependency, premenstrual dysphoricdisorder, or obesity, comprising administering to a mammal in need ofsuch treatment, a therapeutically effective amount of sertraline in asustained-release oral dosage form as defined in claim
 21. 78. A methodfor treating a psychiatric illness, premature ejaculation, chemicaldependency, premenstrual dysphoric disorder, or obesity, comprisingadministering to a mammal in need d such treatment, a therapeuticallyeffective amount of sertraline in a delayed plus sustained-release oraldosage form as defined in claim
 31. 79. A method for treating apsychiatric illness, premature ejaculation, chemical dependency,premenstrual dysphoric disorder, or obesity, comprising administering toa mammal in need of such treatment, a therapeutically effective amountof sertraline in a delayed plus sustained-release oral dosage form asdefined in claim
 36. 80. A method for treating a psychiatric illness,premature ejaculation, chemical dependency, premenstrual dysphoricdisorder, or obesity, comprising administering to a mammal in need ofsuch treatment, a therapeutically effective amount of sertraline in adelayed plus sustained-release oral dosage form as defined in claim 43.81. A method for treating a psychiatric illness, premature ejaculation,chemical dependency, premenstrual dysphoric disorder, or obesity,comprising administering to a mammal in need of such treatment, atherapeutically effective amount of sertraline in a delayed plussustained-release oral dosage form as defined in claim
 54. 82. A methodfor treating a psychiatric illness, premature ejaculation, chemicaldependency, premenstrual dysphoric disorder, or obesity, comprisingadministering to a mammal in need of such treatment, a therapeuticallyeffective amount of sertraline in a delayed plus sustained-release oraldosage form as defined in claim
 60. 83. A method for treating apsychiatic illness, premature ejaculation, chemical dependency,premenstrual dysphoric disorder, or obesity, comprising administering toa mammal in need of such treatment, a therapeutically effective amountof sertraline in a delayed plus sustained-release oral dosage form asdefined in claim
 66. 84. Sertraline acetate.
 85. Sertraline acetate ofclaim 84 having the X-ray crystal structure of FIG.
 1. 86. Sertralineacetate·¼ hydrate.
 87. A pharmaceutical composition comprisingsertraline acetate of claim 84 and a pharmaceutically acceptable carrieror diluent.
 88. A pharmaceutical composition comprising sertralineacetate of claim 85 and a pharmaceutically acceptable carrier ordiluent.
 89. A pharmaceutical composition comprising sertralineacetate·¼ hydrate of claim 86 and a pharmaceutically acceptable carrieror diluent.
 90. Sertraline L-lactate.
 91. Sertraline L-lactate of claim90 having the X-ray crystal structure of FIG.
 3. 92. A pharmaceuticalcomposition comprising sertraline L-lactate of claim 90 and apharmaceutically acceptable carrier or diluent.
 93. A pharmaceuticalcomposition comprising sertraline L-lactate of claim 91 and apharmaceutically acceptable carrier or diluent.
 94. SertralineL-aspartate.
 95. A pharmaceutical composition comprising sertraline ofclaim 11, wherein said sertraline is sertraline L-aspartate and apharmaceutically acceptable carrier or diluent.
 96. A method fortreating a disease or condition selected from anorexia, impulsedisorders, onychophagia, premenstrual syndrome, psychotic disordersschizophrenia inflammatory disorders, hyperactive immune systemdisorders, and chemical dependency in a subject suffering from one ormore of said diseases or conditions comprising administering to saidsubject an effective amount of sertraline acetate, sertraline L-lactateor sertraline L-aspartate.
 97. A method of claim 96 wherein sertralineacetate is administered.
 98. A method of claim 96 wherein sertralineL-lactate is administered.
 99. A method for treating mental depressionin a mentally-depressed subject comprising administering to said subjectan effective amount of sertraline acetate, sertraline L-lactate orsertraline L-aspartate.
 100. A method of claim 99 wherein sertralineacetate is administered.
 101. A method of claim 99 wherein sertralineL-lactate is administered.
 102. A method for treating an anxiety-relateddisorder in a subject suffering therefrom comprising administering tosaid subject an effective amount of sertraline acetate, sertralineL-lactate or sertraline L-aspartate.
 103. A method of claim 102 whereinsaid anxiety-related disorder is obsessive-compulsive disorder.
 104. Amethod of claim 103 wherein sertraline acetate is administered.
 105. Amethod of claim 103 wherein sertraline L-lactate is administered.
 106. Aprocess for preparing sertraline acetate comprising reacting a salt ofsertraline with a base in the presence of a suitable organic solvent toform sertraline free base, partitioning said sertraline free base intoan organic solvent and reacting said sertraline free base with aceticacid in the presence of a suitable organic solvent.
 107. A process ofclaim 106 wherein said salt of sertraline is sertraline hydrochlorideand said solvent is hexane.
 108. A process for preparing sertralineacetate comprising reacting sertraline free base with acetic acid in thepresence of a suitable organic solvent.
 109. A process for preparingsertraline L-lactate comprising reacting a salt of sertraline with abase in the presence of a suitable organic solvent to form sertralinefree base, partitioning said sertraline free base into an organicsolvent and reacting said sertraline free base with L-lactic acid in thepresence of a suitable organic solvent.
 110. A process of claim 109wherein said salt of sertraline is sertraline hydrochloride and saidsolvent is ethyl acetate.
 111. A process of claim 109 wherein said saltof sertraline is sertraline mandelate and said solvent is ethyl acetate.112. A process for sertraline L-lactate comprising reacting sertralinefree base with L-lactic acid in the presence of a suitable organicsolvent.
 113. A process for preparing sertraline L-aspartate comprisingreacting a salt of sertraline with a base in the presence of a suitableorganic solvent to form sertraline free base, partitioning saidsertraline free base into an organic solvent and reacting saidsertraline free base with aspartic acid in the presence of a suitableorganic solvent.
 114. A process of claim 113 wherein said salt ofsertraline is sertraline hydrochloride and said solvent is ethyl acetatesaturated with water.
 115. A process for preparing sertralineL-aspartate comprising reacting sertraline free base with L-asparticacid in the presence of a suitable organic solvent.
 116. The methodaccording to any one of claims 75-83 wherein said mammal is a humanpatient.